Skip to main content
SpringerLink
Log in

Overexpression of YY1 Regulates the Resistance of Cancer Stem Cells: Targeting YY1

  • Chapter
  • First Online:
Cancer Stem Cell Resistance to Targeted Therapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 19))

  • 609 Accesses

Abstract

Most human cancers respond poorly to conventional therapeutics, and those that respond develop resistance to subsequent treatments. It has been reported that in many, but not all, studied cancers, there exists a mini population of cancer stem cells (CSCs) that is highly drug resistant and that its survival leads to recurrences and metastases. Hence, new targeted therapies directed at CSCs have been the subject of many investigations, and several agents are currently being investigated clinically. Several transcription factors are overexpressed in CSCs (e.g., SOX2, OCT4, NANOG, BMI1) that regulate stemness such as pluripotency and also regulate drug resistance. The transcription factor Yin Yang 1 (YY1) has been reported to be overexpressed in many cancers and is associated with cell proliferation, viability, EMT, metastasis, and chemo-immune resistance. Due to many common features of YY1 activities and cancer stem cell transcription factors, it was hypothesized that a crosstalk may exist between YY1 and CSCs transcription factors. Proteomic analysis was performed for the expression of YY1, SOX2, OCT4, and BM1 and delineated the presence of four groups of cancers with different molecular signatures consisting of different levels of expression of the above four transcription factors. These findings supported the hypothesis that YY1 is involved in the regulation of cancer stem cell transcription factors and their roles in resistance. Thus, targeting YY1 alone may be considered as a new therapeutic approach when used alone or in combination with various conventional or novel drugs to reverse cancer resistance in patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BMI-1:

B cell-specific Moloney murine leukemia virus integration site 1

CSC:

Cancer stem cell

EMT:

Epithelial–mesenchymal transition

HDAC:

Histone deacetylases

Nanog:

Nanog homeobox

OCT 4:

Octamer-binding transcription factor 4

RKIP:

Raf kinase inhibitor protein

SOX2:

SRY (sex determining region Y)-box 2

YY1:

Yin Yang 1

References

  1. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675–99.

    Article  CAS  PubMed  Google Scholar 

  2. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  3. Matchett KB, Lappin TR. Concise reviews: cancer stem cells: from concept to cure. Stem Cells. 2014;32(10):2563–70.

    Article  CAS  PubMed  Google Scholar 

  4. Rapp UR, Ceteci F, Schreck R. Oncogene-induced plasticity and cancer stem cells. Cell Cycle. 2008;7(1):45–51.

    Article  CAS  PubMed  Google Scholar 

  5. Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M. Therapies targeting cancer stem cells: current trends and future challenges. World J Stem Cells. 2015;7(9):1185–201.

    PubMed  PubMed Central  Google Scholar 

  6. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8(10):806–23.

    Article  CAS  PubMed  Google Scholar 

  7. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M. Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res. 2014;42(Database issue):D199–205.

    Article  CAS  PubMed  Google Scholar 

  8. Kaufhold S, Garban H, Bonavida B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res. 2016;35:84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Lee SH, Oh SY, Do SI, Lee HJ, Kang HJ, Rho YS, Bae WJ, Lim YC. SOX2 regulates self-renewal and tumorigenicity of stem-like cells of head and neck squamous cell carcinoma. Br J Cancer. 2014;111(11):2122–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Niu CS, Li DX, Liu YH, Fu XM, Tang SF, Li J. Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells. Oncol Rep. 2011;26(3):593–601.

    CAS  PubMed  Google Scholar 

  11. Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H, Nakatsuji N, Tada T. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol. 2005;25(6):2475–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Do HJ, Lee WY, Lim HY, Oh JH, Kim DK, Kim JH, Kim T, Kim JH. Two potent transactivation domains in the C-terminal region of human NANOG mediate transcriptional activation in human embryonic carcinoma cells. J Cell Biochem. 2009;106(6):1079–89.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Q, He W, Lu C, Wang Z, Wang J, Giercksky KE, Nesland JM, Suo Z. Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res. 2009;29(4):1233–41.

    CAS  PubMed  Google Scholar 

  14. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113(5):631–42.

    Article  CAS  PubMed  Google Scholar 

  15. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005 Sep;122(6):947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Siu MK, Wong ES, Kong DS, Chan HY, Jiang L, Wong OG, Lam EW, Chan KK, Ngan HY, Le XF, Cheung AN. Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers. Oncogene. 2013;32(30):3500–9.

    Article  CAS  PubMed  Google Scholar 

  17. Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M, Campisi J, Wazer DE, Band V. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 2002;62(16):4736–45.

    CAS  PubMed  Google Scholar 

  18. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004;113(2):175–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119(12):3626–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vormittag L, Thurnher D, Geleff S, Pammer J, Heiduschka G, Brunner M, Grasl MC, Erovic BM. Co-expression of Bmi-1 and podoplanin predicts overall survival in patients with squamous cell carcinoma of the head and neck treated with radio(chemo)therapy. Int J Radiat Oncol Biol Phys. 2009;73(3):913–8.

    Article  CAS  PubMed  Google Scholar 

  21. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.

    Article  CAS  PubMed  Google Scholar 

  22. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schulenburg A, Blatt K, Cerny-Reiterer S, Sadovnik I, Herrmann H, Marian B, Grunt TW, Zielinski CC, Valent P. Cancer stem cells in basic science and in translational oncology: can we translate into clinical application? J Hematol Oncol. 2015;8:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Okuhashi Y, Itoh M, Nara N, Tohda S. Effects of combination of Notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells. Anticancer Res. 2011;31:893–6.

    CAS  PubMed  Google Scholar 

  25. Sinclair A, Latif AL, Holyoake TL. Targeting survival pathways in chronic myeloid leukaemia stem cells. Br J Pharmacol. 2013;169:1693–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res. 2010;16:3153–62.

    Article  CAS  PubMed  Google Scholar 

  27. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, Miele L. Targeting Notch to target cancer stem cells. Clin Cancer Res. 2010;16:3141–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Merchant AA, Matsui W. Targeting hedgehog - a cancer stem cell pathway. Clin Cancer Res. 2010;16:3130–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang ML, Chiou SH, Wu CW. Targeting cancer stem cells: emerging role of Nanog transcription factor. Onco Targets Ther. 2013;6:1207–20.

    PubMed  PubMed Central  Google Scholar 

  30. Qin S, Li Y, Cao X, Du J, Huang X. NANOG regulates epithelial-mesenchymal transition and chemoresistance in ovarian cancer. Biosci Rep. 2017;37(1). pii: BSR20160247

    Google Scholar 

  31. Li L, Wei X, Wu B, Xiao Y, Yin M, Yang Q. siRNA-mediated knockdown of ID1 disrupts Nanog- and Oct-4-mediated cancer stem cell-likeness and resistance to chemotherapy in gastric cancer cells. Oncol Lett. 2017;13(5):3014–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Song KH, Choi CH, Lee HJ, Oh SJ, Woo SR, Hong SO, Noh KH, Cho H, Chung E, Kim JH, Chung JY, Hewitt SM, Baek S, Lee KM, Yee C, Son M, Mao CP, Wu TC, Kim TW. HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. Cancer Res. 2017;77(18):5039–53. https://doi.org/10.1158/0008-5472.CAN-17-0072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A, Yagishita S, Tajima K, Hidayat M, Shimada N, Suina K, Yoshioka Y, Sasaki S, Moriyama M, Moriyama H, Takahashi K. Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells. Biochem Biophys Res Commun. 2016;473(1):125–32.

    Article  CAS  PubMed  Google Scholar 

  34. Lu CS, Shieh GS, Wang CT, Su BH, Su YC, Chen YC, Su WC, Wu P, Yang WH, Shiau AL, Wu CL. Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer. Oncotarget. 2017;8(19):30844–58.

    PubMed  Google Scholar 

  35. Villodre ES, Kipper FC, Pereira MB, Lenz G. Roles of OCT4 in tumorigenesis, cancer therapy resistance and prognosis. Cancer Treat Rev. 2016;51:1–9.

    Article  CAS  PubMed  Google Scholar 

  36. Gwak JM, Kim M, Kim HJ, Jang MH, Park SY. Expression of embryonal stem cell transcription factors in breast cancer: Oct4 as an indicator for poor clinical outcome and tamoxifen resistance. Oncotarget. 2017;8(22):36305–18.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wuebben EL, Wilder PJ, Cox JL, Grunkemeyer JA, Caffrey T, Hollingsworth MA, Rizzino A. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells. Oncotarget. 2016;7(23):34890–906.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Song WS, Yang YP, Huang CS, Lu KH, Liu WH, Wu WW, Lee YY, Lo WL, Lee SD, Chen YW, Huang PI, Chen MT. Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells. J Chin Med Assoc. 2016;79(10):538–45.

    Article  PubMed  Google Scholar 

  39. Garros-Regulez L, Garcia I, Carrasco-Garcia E, Lantero A, Aldaz P, Moreno-Cugnon L, Arrizabalaga O, Undabeitia J, Torres-Bayona S, Villanua J, Ruiz I, Egaña L, Sampron N, Matheu A. Targeting SOX2 as a therapeutic strategy in glioblastoma. Front Oncol. 2016;6:222.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, Ku SY, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang CH, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355(6320):84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Das T, Nair RR, Green R, Padhee S, Howell M, Banerjee J, Mohapatra SS, Mohapatra S. Actinomycin D down-regulates SOX2 expression and induces death in breast cancer stem cells. Anticancer Res. 2017;37(4):1655–63.

    Article  CAS  PubMed  Google Scholar 

  42. Wuebben EL, Rizzino A. The dark side of SOX2: cancer - a comprehensive overview. Oncotarget. 2017;8(27):44917–43.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tripathi SC, Fahrmann JF, Celiktas M, Aguilar M, Marini KD, Jolly MK, Katayama H, Wang H, Murage EN, Dennison JB, Watkins DN, Levine H, Ostrin EJ, Taguchi A, Hanash SM. MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway. Cancer Res. 2017;77(16):4414–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bartucci M, Hussein MS, Huselid E, Flaherty K, Patrizii M, Laddha SV, Kui C, Bigos RA, Gilleran JA, El Ansary MMS, Awad MAM, Kimball SD, Augeri DJ, Sabaawy HE. Synthesis and characterization of novel BMI1 inhibitors targeting cellular self-renewal in hepatocellular carcinoma. Target Oncol. 2017;12(4):449–62.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chen D, Wu M, Li Y, Chang I, Yuan Q, Ekimyan-Salvo M, Deng P, Yu B, Yu Y, Dong J, Szymanski JM, Ramadoss S, Li J, Wang CY. Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell. 2017;20(5):621–634.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yin T, Zhang Z, Cao B, Duan Q, Shi P, Zhao H, Camara SN, Shen Q, Wang C. Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine. Oncotarget. 2016;7(24):37192–204.

    PubMed  PubMed Central  Google Scholar 

  47. Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012;30(3):372–8.

    Article  CAS  PubMed  Google Scholar 

  48. Naujokat C. Monoclonal antibodies against human cancer stem cells. Immunotherapy. 2014;6(3):290–308.

    Article  CAS  PubMed  Google Scholar 

  49. Swaminathan SK, Roger E, Toti U, Niu L, Ohlfest JR, Panyam J. CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release. 2013;171(3):280–7.

    Article  CAS  PubMed  Google Scholar 

  50. Skubitz AP, Taras EP, Boylan KL, Waldron NN, Oh S, Panoskaltsis-Mortari A, Vallera DA. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecol Oncol. 2013;130(3):579–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Mol Pathol. 1999;52(4):189–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012;109(17):6662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Clayton S, Mousa SA. Therapeutics formulated to target cancer stem cells: is it in our future? Cancer Cell Int. 2011;11:7.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34:732–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Feng D, Wang N, Hu J, Li W. Surface markers of hepatocellular cancer stem cells and their clinical potential. Neoplasma. 2014;61(5):505–13.

    Article  CAS  PubMed  Google Scholar 

  56. Justilien V, Fields AP. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res. 2015;21:505–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zuo M, Rashid A, Churi C, Vauthey JN, Chang P, Li Y, Hung MC, Li D, Javle M. Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer. Br J Cancer. 2015;112:1042–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang X, Lou Y, Zheng X, Wang H, Sun J, Dong Q, Han B. Wnt blockers inhibit the proliferation of lung cancer stem cells. Drug Des Devel Ther. 2015;9:2399–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gargini R, Cerliani JP, Escoll M, Antón IM, Wandosell F. Cancer stem cell-like phenotype and survival are coordinately regulated by Akt/FoxO/Bim pathway. Stem Cells. 2015;33:646–60.

    Article  CAS  PubMed  Google Scholar 

  61. Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013;4:e875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dong P, Konno Y, Watari H, Hosaka M, Noguchi M, Sakuragi N. The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer. J Transl Med. 2014;12:231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Liu L, Salnikov AV, Bauer N, Aleksandrowicz E, Labsch S, Nwaeburu C, Mattern J, Gladkich J, Schemmer P, Werner J, et al. Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-κB downregulation. Int J Cancer. 2014;134:2489–503.

    Article  CAS  PubMed  Google Scholar 

  64. Panneerselvam J, Jin J, Shanker M, Lauderdale J, Bates J, Wang Q, Zhao YD, Archibald SJ, Hubin TJ, Ramesh R. IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. PLoS One. 2015;10:e0122439.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Singh B, Cook KR, Martin C, Huang EH, Mosalpuria K, Krishnamurthy S, Cristofanilli M, Lucci A. Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer. Clin Exp Metastasis. 2010;27:233–40.

    Article  CAS  PubMed  Google Scholar 

  66. Drenckhan A, Kurschat N, Dohrmann T, Raabe N, Koenig AM, Reichelt U, Kaifi JT, Izbicki JR, Gros SJ. Effective inhibition of metastases and primary tumor growth with CTCE-9908 in esophageal cancer. J Surg Res. 2013;182:250–6.

    Article  CAS  PubMed  Google Scholar 

  67. Hoellenriegel J, Zboralski D, Maasch C, Rosin NY, Wierda WG, Keating MJ, Kruschinski A, Burger JA. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood. 2014;123:1032–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Burkhardt JK, Hofstetter CP, Santillan A, Shin BJ, Foley CP, Ballon DJ, Pierre Gobin Y, Boockvar JA. Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench. J Clin Neurosci. 2012;19:1568–72.

    Article  CAS  PubMed  Google Scholar 

  69. Gillespie DL, Aguirre MT, Ravichandran S, Leishman LL, Berrondo C, Gamboa JT, Wang L, King R, Wang X, Tan M, et al. RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model. J Neurosurg. 2015;122:331–41.

    Article  PubMed  Google Scholar 

  70. Chamie K, Klöpfer P, Bevan P, Störkel S, Said J, Fall B, Belldegrun AS, Pantuck AJ. Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial. Urol Oncol. 2015;33:204.e25–33.

    Article  CAS  Google Scholar 

  71. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24:506–13.

    Article  CAS  PubMed  Google Scholar 

  72. Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr Opin Cell Biol. 2009;21:452–60.

    Article  CAS  PubMed  Google Scholar 

  73. Garg M. MicroRNAs, stem cells and cancer stem cells. World J Stem Cells. 2012;4:62–70.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282:14328–36.

    Article  CAS  PubMed  Google Scholar 

  75. Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat. 2008;111:419–27.

    Article  CAS  PubMed  Google Scholar 

  76. Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ, Jordan CT. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A. 2002;99:16220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ginestier C, Wicinski J, Cervera N, Monville F, Finetti P, Bertucci F, Wicha MS, Birnbaum D, Charafe-Jauffret E. Retinoid signaling regulates breast cancer stem cell differentiation. Cell Cycle. 2009;8:3297–302.

    Article  CAS  PubMed  Google Scholar 

  78. Salvador MA, Wicinski J, Cabaud O, Toiron Y, Finetti P, Josselin E, Lelièvre H, Kraus-Berthier L, Depil S, Bertucci F, et al. The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression. Clin Cancer Res. 2013;19:6520–31.

    Article  CAS  PubMed  Google Scholar 

  79. Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene. 2006;25(8):1125–42.

    Article  CAS  PubMed  Google Scholar 

  80. Sui G, Affar el B, Shi Y, Brignone C, Wall NR, Yin P, Donohoe M, Luke MP, Calvo D, Grossman SR, Shi Y. Yin Yang 1 is a negative regulator of p53. Cell. 2004;117(7):859–72.

    Article  CAS  PubMed  Google Scholar 

  81. Gao F, Wei Z, An W, Wang K, Lu W. The interactomes of POU5F1 and SOX2 enhancers in human embryonic stem cells. Sci Rep. 2013;3:1588.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Satijn DP, Hamer KM, den Blaauwen J, Otte AP. The polycomb group protein EED interacts with YY1, and both proteins induce neural tissue in Xenopus embryos. Mol Cell Biol. 2001;21(4):1360–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang AM, Huang TT, Hsu KW, Huang KH, Fang WL, Yang MH, Lo SS, Chi CW, Lin JJ, Yeh TS. Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis. Oncotarget. 2014;5(13):5002–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

    Article  PubMed  CAS  Google Scholar 

  85. Zhang Q, Stovall DB, Inoue K, Sui G. The oncogenic role of Yin Yang 1. Crit Rev Oncog. 2011;16(3–4):163–97.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li D, Wang W, Sui G. YY1 is an inducer of cancer metastasis. Crit Rev Oncog. 2017;22(1–2):1–11.

    PubMed  Google Scholar 

  87. Katsushima K, Natsume A, Ohka F, Shinjo K, Hatanaka A, Ichimura N, Sato S, Takahashi S, Kimura H, Totoki Y, Shibata T, Naito M, Kim HJ, Miyata K, Kataoka K, Kondo Y. Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment. Nat Commun. 2016;7:13616.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Bonavida B. Therapeutic Ying Yang 1 (YY1) inhibitors in cancer: ALL in ONE. Crit Rev Oncog. 2017;22:37.

    Article  PubMed  Google Scholar 

  89. Aguilera O, Muñoz A, Esteller M, Fraga MF. Epigenetic alterations of the Wnt/beta-catenin pathway in human disease. Endocr Metab Immune Disord Drug Targets. 2007;7:13–21.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MT, Wang H, Chen J, Ng SS, Chen M, Sung JJ, Yu J. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene. 2013;32:5078–88.

    Article  CAS  PubMed  Google Scholar 

  91. Zhou WY, Chen JC, Jiao TT, Hui N, Qi X. MicroRNA-181 targets Yin Yang 1 expression and inhibits cervical cancer progression. Mol Med Rep. 2015;11(6):4541–6.

    Article  CAS  PubMed  Google Scholar 

  92. Nie J, Ge X, Geng Y, Cao H, Zhu W, Jiao Y, Wu J, Zhou J, Cao J. miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1. Oncol Rep. 2015;34:311–7.

    Article  CAS  PubMed  Google Scholar 

  93. Alakurtti S, Makela T, Koskimies S, Yli-Kauhaluoma J. Pharmacological properties of the ubiquitous natural product betulin. Eur. J. Pharm. Sci. 29. 2006; 1–13.

    Article  CAS  PubMed  Google Scholar 

  94. Fulda S. Betulinic Acid for Cancer Treatment and Prevention. International Journal of Molecular Sciences. 2008;9(6):1096–1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu X, Jutooru I, Lei P, Kim K, Lee SO, Brents LK, Prather PL, Safe S. Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther. 2012;11:1421–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bonavida B, Garban H. Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics. Redox Biol. 2015;6:486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang YL, Guang MH, Zhuo HQ, Min XH, Yao Q, Gu AQ, Wu SH, Zhang DB, Lu JY, Chen Y, Chen YH, Zhang KJ. Carfilzomib inhibits constitutive NF-κB activation in mantle cell lymphoma B cells and leads to the induction of apoptosis. Acta Haematol. 2017;137(2):106–12.

    Article  CAS  PubMed  Google Scholar 

  98. Ettari R, Zappalà M, Grasso S, Musolino C, Innao V, Allegra A. Immunoproteasome-selective and non-selective inhibitors: a promising approach for the treatment of multiple myeloma. Pharmacol Ther. 2018;182:176–92. pii: S0163-7258(17)30235–8.

    Article  CAS  Google Scholar 

  99. Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14(7):417–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Citrin R, Foster JB, Teachey DT. The role of proteasome inhibition in the treatment of malignant and non-malignant hematologic disorders. Expert Rev Hematol. 2016;9(9):873–89.

    Article  CAS  PubMed  Google Scholar 

  101. Potts BC, Albitar MX, Anderson KC, Baritaki S, Berkers C, Bonavida B, Chandra J, Chauhan D, Cusack JC Jr, Fenical W, Ghobrial IM, Groll M, Jensen PR, Lam KS, Lloyd GK, McBride W, McConkey DJ, Miller CP, Neuteboom ST, Oki Y, Ovaa H, Pajonk F, Richardson PG, Roccaro AM, Sloss CM, Spear MA, Valashi E, Younes A, Palladino MA. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets. 2011;11(3):254–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sanchez E, Li M, Steinberg JA, Wang C, Shen J, Bonavida B, Li ZW, Chen H, Berenson JR. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol. 2010;148(4):569–81.

    Article  CAS  PubMed  Google Scholar 

  103. Vaisitti T, Gaudino F, Ouk S, Moscvin M, Vitale N, Serra S, Arruga F, Zakrzewski JL, Liou HC, Allan JN, Furman RR, Deaglio S. Targeting metabolism and survival in chronic lymphocytic leukemia and Richter syndrome cells by a novel NF-kB inhibitor. Haematologica. 2017;102(11):1878–89. pii: haematol.2017.173419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Qian C, Chen X, Qi Y, Zhong S, Gao X, Zheng W, Mao Z, Yao J. Sporamin induces apoptosis and inhibits NF-κB activation in human pancreatic cancer cells. Tumour Biol. 2017;39(7):1010428317706917.

    Article  PubMed  Google Scholar 

  105. Ukaji T, Lin Y, Okada S, Umezawa K. Inhibition of MMP-2-mediated cellular invasion by NF-κB inhibitor DHMEQ in 3D culture of breast carcinoma MDA-MB-231 cells: a model for early phase of metastasis. Biochem Biophys Res Commun. 2017;485(1):76–81. https://doi.org/10.1016/j.bbrc.2017.02.022.

    Article  CAS  PubMed  Google Scholar 

  106. Katsman A, Umezawa K, Bonavida B. Reversal of resistance to cytotoxic cancer therapies: DHMEQ as a chemo-sensitizing and immuno-sensitizing agent. Drug Resist Updat. 2007;10(1–2):1–12.

    Article  CAS  PubMed  Google Scholar 

  107. Lee C, Kim BG, Kim JH, Chun J, Im JP, Kim JS. Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. Int Immunopharmacol. 2017;51:47–56. https://doi.org/10.1016/j.intimp.2017.07.023.

    Article  CAS  PubMed  Google Scholar 

  108. Wang G, Li J, Zhang L, Huang S, Zhao X, Zhao X. Celecoxib induced apoptosis against different breast cancer cell lines by down-regulated NF-κB pathway. Biochem Biophys Res Commun. 2017;490(3):969–76.

    Article  CAS  PubMed  Google Scholar 

  109. Nunes JJ, Pandey SK, Yadav A, Goel S, Ateeq B. Targeting NF-kappa B signaling by artesunate restores sensitivity of castrate-resistant prostate cancer cells to antiandrogens. Neoplasia. 2017;19(4):333–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yang CM, Chen YW, Chi PL, Lin CC, Hsiao LD. Resveratrol inhibits BK-induced COX-2 transcription by suppressing acetylation of AP-1 and NF-κB in human rheumatoid arthritis synovial fibroblasts. Biochem Pharmacol. 2017;132:77–91.

    Article  CAS  PubMed  Google Scholar 

  111. Durand JK, Baldwin AS. Targeting IKK and NF-κB for therapy. Adv Protein Chem Struct Biol. 2017;107:77–115.

    Article  CAS  PubMed  Google Scholar 

  112. de Castro Barbosa ML, da Conceicao RA, Fraga AGM, Camarinha BD, de Carvalho Silva GC, Lima AGF, Cardoso EA, de Oliveira Freitas Lione V. NF-κB signaling pathway inhibitors as anticancer drug candidates. Anti Cancer Agents Med Chem. 2017;17(4):483–90.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The author acknowledges the assistance of the Jonsson Comprehensive Cancer Center at UCLA and the Department of Microbiology, Immunology, and Molecular Genetics. He also acknowledges both Samantha Kaufhold and Hermes Garban for their involvement in reference [8] from which this review chapter has utilized many of the main findings. The assistance of Arah Cho and Leah Moyal are gratefully acknowledged for their help in the preparation of the manuscript.

Conflicts of Interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Benjamin Bonavida

Authors
  1. Benjamin Bonavida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin Bonavida .

Editor information

Editors and Affiliations

  1. Research Department, Sidra Medicine, Doha, Qatar

    Cristina Maccalli

  2. Department of DIBIMIS, University of Palermo, Laboratory of Cellular and Molecular Pathophysiology, Palermo, Italy

    Matilde Todaro

  3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Soldano Ferrone

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bonavida, B. (2019). Overexpression of YY1 Regulates the Resistance of Cancer Stem Cells: Targeting YY1. In: Maccalli, C., Todaro, M., Ferrone, S. (eds) Cancer Stem Cell Resistance to Targeted Therapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-16624-3_4

Download citation

Publish with us

Policies and ethics

Search

Navigation