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KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner

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Abstract

Most N6-methyladenosine (m6A) associated regulatory proteins (i.e., m6A writer, eraser, and reader proteins) are involved in the pathogenesis of various cancers, mostly in m6A-dependent manners. As a component in the m6A ‘writers’, KIAA1429 is reported to be an RNA-binding protein and involved in the m6A modification, mRNA splicing and processing. Till now, the functions of KIAA1429 in tumorigenesis and related mechanism have not been reported. In the present study, we found KIAA1429 was highly expressed in breast cancer tissues, but frequently down-regulated in non-cancerous breast tissues. The overall survival of breast cancer patients with high-expression KIAA1429 was significantly shorter than those with low-expression KIAA1429. Then, we demonstrated that KIAA1429 was associated with breast cancer proliferation and metastasis in vivo and in vitro. The potential targeting genes of KIAA1429 in breast cancer were identified by RNA immunoprecipitation sequencing. One of these genes is cyclin-dependent kinase 1 (CDK1), which plays an oncogenic role in cancers. Furthermore, we confirmed that KIAA1429 played its oncogenic role in breast cancer by regulating CDK1 by an m6A-independent manner. 5′-fluorouracil was found to be very effective in reducing the expression of KIAA1429 and CDK1 in breast cancer. These findings indicated that KIAA1429 could promote breast cancer progression and was correlated with pathogenesis. It may represent a promising therapeutic strategy on breast cancer, especially in combination with CDK1 treatment.

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References

  1. Tsai WC, Chu CH, Yu CP, Sheu LF, Chen A, Chiang H, et al. Matriptase and survivin expression associated with tumor progression and malignant potential in breast cancer of Chinese women: tissue microarray analysis of immunostaining scores with clinicopathological parameters. Dis Markers. 2008;24:89–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29:1343–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet. 2014;15:293–306.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42.

    Article  CAS  PubMed  Google Scholar 

  6. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.

    Article  PubMed  Google Scholar 

  7. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, et al. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507–19.

    Article  CAS  PubMed  Google Scholar 

  8. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell. 2013;155:793–806.

    Article  CAS  PubMed  Google Scholar 

  9. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 2014;8:284–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, et al. m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature. 2016;540:301–4.

    Article  CAS  PubMed  Google Scholar 

  13. Guo J, Tang HW, Li J, Perrimon N, Yan D. Xio is a component of the Drosophila sex determination pathway and RNA N(6)-methyladenosine methyltransferase complex. Proc Natl Acad Sci USA. 2018;115:3674–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tang C, Klukovich R, Peng H, Wang Z, Yu T, Zhang Y, et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells. Proc Natl Acad Sci USA. 2018;115:E325–33.

    Article  CAS  PubMed  Google Scholar 

  15. Pan Y, Ma P, Liu Y, Li W, Shu Y. Multiple functions of m(6)A RNA methylation in cancer. J Hematol Oncol. 2018;11:48.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dai D, Wang H, Zhu L, Jin H, Wang X. N6-methyladenosine links RNA metabolism to cancer progression. Cell death Dis. 2018;9:124.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang S, Sun C, Li J, Zhang E, Ma Z, Xu W, et al. Roles of RNA methylation by means of N(6)-methyladenosine (m(6)A) in human cancers. Cancer Lett. 2017;408:112–20.

    Article  CAS  PubMed  Google Scholar 

  18. Fry NJ, Law BA, Ilkayeva OR, Carraway KR, Holley CL, Mansfield KD. N(6)-methyladenosine contributes to cellular phenotype in a genetically-defined model of breast cancer progression. Oncotarget. 2018;9:31231–43.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Panneerdoss S, Eedunuri VK, Yadav P, Timilsina S, Rajamanickam S, Viswanadhapalli S, et al. Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression. Sci Adv. 2018;4:eaar8263.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552:126–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018;415:11–9.

    Article  CAS  PubMed  Google Scholar 

  22. Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2018;67:2254–70.

    Article  CAS  PubMed  Google Scholar 

  23. Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017;65:529–43.

    Article  CAS  PubMed  Google Scholar 

  24. Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018;37:522–33.

    Article  CAS  PubMed  Google Scholar 

  25. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, et al. m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18:2622–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.

    Article  PubMed  Google Scholar 

  27. Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172:90–105 e123.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31:591–606 e596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 2016;113:E2047–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang C, Zhi WI, Lu H, Samanta D, Chen I, Gabrielson E, et al. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217 and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget 2016;7:64527–42.

    PubMed  PubMed Central  Google Scholar 

  31. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 2016;62:335–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell. 2018;69:1028–38 e1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Knuckles P, Lence T, Haussmann IU, Jacob D, Kreim N, Carl SH, et al. Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes Dev. 2018;32:415–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation. Cell Disco. 2018;4:10.

    Article  Google Scholar 

  35. Niessen M, Schneiter R, Nothiger R. Molecular identification of virilizer, a gene required for the expression of the sex-determining gene Sex-lethal in Drosophila melanogaster. Genetics. 2001;157:679–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Garcia-Maurino SM, Rivero-Rodriguez F, Velazquez-Cruz A, Hernandez-Vellisca M, Diaz-Quintana A, De la Rosa MA, et al. RNA binding protein regulation and cross-talk in the control of AU-rich mRNA fate. Front Mol Biosci. 2017;4:71.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dassi E. Handshakes and fights: the regulatory interplay of RNA-binding proteins. Front Mol Biosci. 2017;4:67.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hong S. RNA binding protein as an emerging therapeutic target for cancer prevention and treatment. J Cancer Prev. 2017;22:203–10.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448:811–5.

    Article  CAS  PubMed  Google Scholar 

  40. Payton M, Chung G, Yakowec P, Wong A, Powers D, Xiong L, et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res. 2006;66:4299–308.

    Article  CAS  PubMed  Google Scholar 

  41. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  42. Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15:122.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30:630–41.

    Article  CAS  PubMed  Google Scholar 

  44. Chen X, Zhang FH, Chen QE, Wang YY, Wang YL, He JC, et al. The clinical significance of CDK1 expression in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2015;20:e7–12.

    Article  PubMed  Google Scholar 

  45. Gao SY, Li J, Qu XY, Zhu N, Ji YB. Downregulation of Cdk1 and cyclinB1 expression contributes to oridonin-induced cell cycle arrest at G2/M phase and growth inhibition in SGC-7901 gastric cancer cells. Asian Pac J Cancer Prev. 2014;15:6437–41.

    Article  PubMed  Google Scholar 

  46. Kim SJ, Nakayama S, Miyoshi Y, Taguchi T, Tamaki Y, Matsushima T, et al. Determination of the specific activity of CDK1 and CDK2 as a novel prognostic indicator for early breast cancer. Ann Oncol. 2008;19:68–72.

    Article  CAS  PubMed  Google Scholar 

  47. Jiang G, Zhang S, Yazdanparast A, Li M, Pawar AV, Liu Y, et al. Comprehensive comparison of molecular portraits between cell lines and tumors in breast cancer. BMC Genom. 2016;17(Suppl 7):525.

    Article  Google Scholar 

  48. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  49. Tang J, Wang F, Cheng G, Si S, Sun X, Han J, et al. Wilms’ tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability. J Exp Clin cancer Res. 2018;37:40.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G. Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013;8:176–89.

    Article  CAS  PubMed  Google Scholar 

  51. Jiang H, Lei R, Ding SW, Zhu S. Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads. BMC Bioinforma. 2014;15:182.

    Article  Google Scholar 

  52. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mao X, Cai T, Olyarchuk JG, Wei L. Automated genome annotation and pathway identification using the KEGG Orthology (KO) as a controlled vocabulary. Bioinformatics. 2005;21:3787–93.

    Article  CAS  PubMed  Google Scholar 

  55. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008;36:D480–4.

    Article  CAS  PubMed  Google Scholar 

  56. Jiao X, Sherman BT, Huang da W, Stephens R, Baseler MW, Lane HC, et al. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012;28:1805–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [grant numbers 81572595, 81572607, 81602336], and the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. These authors contributed equally: Jia-Yi Qian, Jian Gao, Xi Sun

Authors and Affiliations

  1. Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, China

    Jia-Yi Qian, Xi Sun, Liang Shi, Tian-Song Xia, Wen-Bin Zhou, Shui Wang & Qiang Ding

  2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China

    Jian Gao

  3. Research Division of Clinical Pharmacology, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, China

    Meng-Da Cao & Ji-Fu Wei

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  1. Jia-Yi Qian
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Qian, JY., Gao, J., Sun, X. et al. KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene 38, 6123–6141 (2019). https://doi.org/10.1038/s41388-019-0861-z

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