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CYP2C9 inhibits the invasion and migration of esophageal squamous cell carcinoma via downregulation of HDAC

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Abstract

Cytochrome P450 2C9 (CYP2C9) is involved in the metabolism of cancer drugs and exogenous carcinogens. In our study, CYP2C9 was downregulated in multiple cohorts of human esophageal squamous cell carcinoma (ESCC). Until now, its role and epigenetic regulation of CYP2C9 repression in ESCC remain poorly understood. CYP2C9 repression in collected ESCC patient tumor tissues was demonstrated by RT-qPCR and Western blot. The histone acetylation level was carried out by the treatment of histone deacetylase inhibitor TSA and RNA interference. Epigenetic analysis revealed that the increased expression of CYP2C9 in KYSE-150 and TE1 cells was characterized by inhibition of HDAC8 and HDAC1, respectively. TSA decreased the levels of HDAC occupancy around CYP2C9 promoter region greatly. Overexpression of CYP2C9 reduced the invasion and migration of ESCC cells.

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Data availability

The datasets obtained and analyzed during the current study were available from the corresponding authors in a reasonable request.

Abbreviations

ESCC:

Esophageal squamous cell carcinoma

CYP2C9:

Cytochrome P450 2C9

HDAC:

Histone deacetylase

siRNAs:

Small interfering RNAs

FCM:

Flow Cytometry

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2015) Cancer statistics in China. CA Cancer J Clin 66(2):115–132

    Article  CAS  Google Scholar 

  3. Fujita H, Kakegawa T, Yamana H, Shima I, Toh Y, Tomita Y, Fujii T, Yamasaki K, Higaki K, Noake T, Ishibashi N, Mizutani K (1995) Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer. Comparison of three-field lymphadenectomy with two-field lymphadenectomy. Ann Surg 222(5):654–662

    Article  CAS  Google Scholar 

  4. Gonzalez FJ, Gelboin HV (1994) Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab Rev 26(1–2):165–183

    Article  CAS  Google Scholar 

  5. Jiang F, Chen L, Yang YC, Wang XM, Wang RY, Li L, Wen W, Chang YX, Chen CY, Tang J, Liu G, Huang WT, Xu L, Wang HY (2015) CYP3A5 functions as a tumor suppressor in hepatocellular carcinoma by regulating mTORC2/Akt signaling. Cancer Res 75(7):1470–1481

    Article  CAS  Google Scholar 

  6. Rodriguez-Antona C, Gomez A, Karlgren M, Sim SC, Ingelman-Sundberg M (2010) Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment. Hum Genet 127(1):1–17

    Article  CAS  Google Scholar 

  7. Yokose T, Doy M, Taniguchi T, Shimada T, Kakiki M, Matsuzaki Y, Mukai K (1999) Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues. Virchows Arch 434(5):401–411

    Article  CAS  Google Scholar 

  8. Lee SJ, Usmani KA, Chanas B, Ghanayem B, Xi T, Hodgson E, Mohrenweiser HW, Goldstein JA (2003) Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics 13(8):461–472

    Article  CAS  Google Scholar 

  9. Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54(10):1271–1294

    Article  CAS  Google Scholar 

  10. Schmelzle M, Dizdar L, Matthaei H, Baldus SE, Wolters J, Lindenlauf N, Bruns I, Cadeddu RP, Kröpil F, Topp SA, Esch JS 2nd, Eisenberger CF, Knoefel WT, Stoecklein NH (2011) Esophageal cancer proliferation is mediated by cytochrome P450 2C9 (CYP2C9). Prostaglandins Other Lipid Mediat 94(1–2):25–33

    Article  CAS  Google Scholar 

  11. Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin D, Wang DW (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 65(11):4707–4715

    Article  CAS  Google Scholar 

  12. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428

    Article  CAS  Google Scholar 

  13. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159

    Article  CAS  Google Scholar 

  14. Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27

    Article  CAS  Google Scholar 

  15. Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, Asanuma M, Funada M, Kiryu K, Naito S, Yoshida Y, Yamamoto S, Hanioka N (2006) Oxidative metabolism of 5-methoxy-N, N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes. Biochem Pharmacol 71(9):1377–1385

    Article  CAS  Google Scholar 

  16. Codd R, Braich N, Liu J, Soe CZ, Pakchung AA (2009) Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 41(4):736–739

    Article  CAS  Google Scholar 

  17. Guo Z, Johnson V, Barrera J, Porras M, Hinojosa D, Hernández I, McGarrah P, Potter DA (2018) Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them. Cancer Metastasis Rev 37(2–3):409–423

    Article  CAS  Google Scholar 

  18. Osanai M, Sawada N, Lee GH (2010) Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1. Oncogene 29(8):1135–1144

    Article  CAS  Google Scholar 

  19. Yu Z, Tian X, Peng Y, Sun Z, Wang C, Tang N, Li B, Jian Y, Wang W, Huo X, Ma X (2018) Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin-induced apoptosis in neural cancer cells. J Pineal Res 65(1):e12478

    Article  Google Scholar 

  20. Zhou C, Huang J, Li Q, Zhan C, Xu X, Zhang X, Ai D, Zhu Y, Wen Z, Wang D (2018) CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis. Free Radic Biol Med 117:168–179

    Article  CAS  Google Scholar 

  21. Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Rodriguez-Lescure A, Agundez JA (2002) Influence of cytochrome P450 CYP2C9 genotypes in lung cancer risk. Cancer Lett 180(1):41–46

    Article  CAS  Google Scholar 

  22. Sausville LN, Gangadhariah MH, Chiusa M, Mei S, Wei S, Zent R, Luther J, Shuey M, Capdevila J, Falck J, Guengerich F, Williams S, Pozzi A (2018) The cytochrome P450 slow metabolizers CYP2C9*2 and CYP2C9*3 directly regulate tumorigenesis via reduced epoxyeicosatrienoic acid production. Cancer Res 78(17):4865–4877

    Article  CAS  Google Scholar 

  23. Samowitz WS, Wolff RK, Curtin K, Sweeney C, Ma KN, Andersen K, Levin TR, Slattery ML (2006) Interactions between CYP2C9 and UGT1A6 polymorphisms and nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Clin Gastroenterol Hepatol 4(7):894–901

    Article  CAS  Google Scholar 

  24. Bergheim I, Wolfgarten E, Bollschweiler E, Hölscher A, Bode C, Parlesak A (2007) Cytochrome P450 levels are altered in patients with esophageal squamous-cell carcinoma. World J Gastroenterol 13(7):997–1002

    Article  CAS  Google Scholar 

  25. Makia N, Surapureddi S, Monostory K, Prough R, Goldstein J (2014) Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and dna looping. Mol Pharmacol 86(2):125–137

    Article  Google Scholar 

  26. Sahi J, Shord S, Lindley C, Ferguson S, LeCluyse E (2009) Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes. J Biochem Mol Toxicol 23(1):43–58

    Article  CAS  Google Scholar 

  27. Chaloin S, Daujat M, Pascussi J, Garcia L, Vilarem M, Maurel P (2002) Transcriptional regulation of CYP2C9 gene role of glucocorticoid receptor and constitutive androstane receptor. J Biol Chem 277(1):209–217

    Article  Google Scholar 

  28. Chen Y, Kissling G, Negishi M, Goldstein J (2005) The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. Pharmacol Exp Ther 314(3):1125–1133

    Article  CAS  Google Scholar 

  29. Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, Kohno T (2016) Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov 6(4):430–445

    Article  CAS  Google Scholar 

  30. Zhu Q, Yu L, Qin Z, Chen L, Hu H, Zheng X, Zeng S (2019) Regulation of OCT2 transcriptional repression by histone acetylation in renal cell carcinoma. Epigenetics 14(8):791–803

    Article  Google Scholar 

  31. Yang W, Hsu C, Hsu T, Liou J, Chang K, Chen P, Liu J, Yang S, Wang J, Yeh S, Chen R, Chang W, Chuang J (2020) Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/noaa103

    Article  PubMed  PubMed Central  Google Scholar 

  32. Al-Dhfyan A, Alhoshani A, Korashy H (2017) Aryl Hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-catenin and Akt activation. Mol Cancer 16(1):14

    Article  Google Scholar 

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Funding

This work was financially supported by National Natural Science Foundation of China (No. 81702801), Hangzhou City Scientific Technology Research Foundation of Zhejiang Province, China (No. 20180533B67), China Postdoctoral Science Foundation (No. 2020M680130), Zhejiang Provincial Natural Sciences Foundation of China (No. LY18H310012), and Zhejiang Provincial Natural Sciences Foundation of China (No. LGF19H310001).

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Author notes

  1. Zhenzhen Jiang and Xiaoli Zheng have contributed equally to the work reported in this manuscript.

Authors and Affiliations

  1. Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China

    Zhenzhen Jiang, Xiaoli Zheng, Liqing Qiu, Lingrong Yang & Mingfeng Jiang

  2. Department of Pharmacy, Hangzhou Cancer Hospital, Hangzhou, 310002, Zhejiang, China

    Weijia Wang & Yuhui Hua

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  1. Zhenzhen Jiang
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  2. Xiaoli Zheng
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Contributions

ZJ and XZ performed most of the experiments and wrote the manuscript. MJ and WW wrote and revised a part of the manuscript. LQ and LY performed Western blotting and qRT-PCR analysis. YH designed and supervised the study.

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Correspondence to Yuhui Hua.

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This project was approved by the Institutional Review Board of Hangzhou Cancer Hospital (Permit Number: HZCH-2016-02).

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Jiang, Z., Zheng, X., Wang, W. et al. CYP2C9 inhibits the invasion and migration of esophageal squamous cell carcinoma via downregulation of HDAC. Mol Cell Biochem 476, 2011–2020 (2021). https://doi.org/10.1007/s11010-021-04050-3

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