ALKBH5 Inhibited Cell Proliferation and Sensitized Bladder Cancer Cells to Cisplatin by M6A-CK2α-Mediated Glycolysis

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2020 Dec 30

PMID 33376625

Citations 89

Authors

Hao Yu

Xiao Yang

Jinyuan Tang

Shuhui Si

Zijian Zhou

Jiancheng Lu

Jie Han

Baorui Yuan

Qikai Wu

Qiang Lu

Haiwei Yang

Affiliations

Soon will be listed here.

Abstract

N6-methyladenosine (m6A) is the most commonly occurring internal RNA modification to be found in eukaryotic mRNA and serves an important role in various physiological events. AlkB homolog 5 RNA demethylase (ALKBH5), an m6A demethylase, belongs to the AlkB family of dioxygenases and has been shown to specifically demethylate m6A in RNA, which is associated with a variety of tumors. However, its function in bladder cancer remains largely unclear. In the present study, we found that the expression of ALKBH5 was downregulated in bladder cancer tissues and cell lines. Low expression of ALKBH5 was correlated with the worse prognosis of bladder cancer patients. Furthermore, functional assays revealed that knockdown of ALKBH5 promoted bladder cancer cell proliferation, migration, invasion, and decreased cisplatin chemosensitivity in the 5637 and T24 bladder cancer cell lines and , whereas ALKBH5 overexpression led to the opposite results. Finally, ALKBH5 inhibited the progression and sensitized bladder cancer cells to cisplatin through a casein kinase 2 (CK2)α-mediated glycolysis pathway in an m6A-dependent manner. Taken together, these findings might provide fresh insights into bladder cancer therapy.

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References

Chen C, Shyu A . Emerging Themes in Regulation of Global mRNA Turnover in cis. Trends Biochem Sci. 2016; 42(1):16-27. PMC: 5182187. DOI: 10.1016/j.tibs.2016.08.014. View

Rabalski A, Gyenis L, Litchfield D . Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells. Clin Cancer Res. 2016; 22(12):2840-7. DOI: 10.1158/1078-0432.CCR-15-1314. View

Yue Y, Liu J, He C . RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015; 29(13):1343-55. PMC: 4511210. DOI: 10.1101/gad.262766.115. View

Xiao W, Adhikari S, Dahal U, Chen Y, Hao Y, Sun B . Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell. 2016; 61(4):507-519. DOI: 10.1016/j.molcel.2016.01.012. View

Bertero A, Brown S, Madrigal P, Osnato A, Ortmann D, Yiangou L . The SMAD2/3 interactome reveals that TGFβ controls mA mRNA methylation in pluripotency. Nature. 2018; 555(7695):256-259. PMC: 5951268. DOI: 10.1038/nature25784. View

Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H . Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell. 2019; 35(4):677-691.e10. PMC: 6812656. DOI: 10.1016/j.ccell.2019.03.006. View

Schwartz S, Mumbach M, Jovanovic M, Wang T, Maciag K, Bushkin G . Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites. Cell Rep. 2014; 8(1):284-96. PMC: 4142486. DOI: 10.1016/j.celrep.2014.05.048. View

Zhang S, Zhao B, Zhou A, Lin K, Zheng S, Lu Z . mA Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell. 2017; 31(4):591-606.e6. PMC: 5427719. DOI: 10.1016/j.ccell.2017.02.013. View

Chen Y, Peng C, Chen J, Chen D, Yang B, He B . WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 2019; 18(1):127. PMC: 6704583. DOI: 10.1186/s12943-019-1053-8. View

10.

Chen F, Huang X, Wu M, Gou S, Hu W . A CK2-targeted Pt(IV) prodrug to disrupt DNA damage response. Cancer Lett. 2016; 385:168-178. DOI: 10.1016/j.canlet.2016.10.026. View

11.

Im D, Cheong H, Lee J, Oh M, Yang K . Protein kinase CK2-dependent aerobic glycolysis-induced lactate dehydrogenase A enhances the migration and invasion of cancer cells. Sci Rep. 2019; 9(1):5337. PMC: 6441004. DOI: 10.1038/s41598-019-41852-4. View

12.

Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes J, Cochet C . Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer. 2007; 43(5):928-34. DOI: 10.1016/j.ejca.2006.11.021. View

13.

Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, OBrien S . CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010; 70(24):10288-98. DOI: 10.1158/0008-5472.CAN-10-1893. View

14.

Tao J, Lu Q, Wu D, Li P, Xu B, Qing W . microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol Rep. 2011; 25(6):1721-9. DOI: 10.3892/or.2011.1245. View

15.

Yang S, Wei J, Cui Y, Park G, Shah P, Deng Y . mA mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019; 10(1):2782. PMC: 6592937. DOI: 10.1038/s41467-019-10669-0. View

16.

Visvanathan A, Patil V, Arora A, Hegde A, Arivazhagan A, Santosh V . Essential role of METTL3-mediated mA modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2017; 37(4):522-533. DOI: 10.1038/onc.2017.351. View

17.

Geula S, Moshitch-Moshkovitz S, Dominissini D, AlFatah Mansour A, Kol N, Salmon-Divon M . Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science. 2015; 347(6225):1002-6. DOI: 10.1126/science.1261417. View

18.

Zhu H, Gan X, Jiang X, Diao S, Wu H, Hu J . ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2. J Exp Clin Cancer Res. 2019; 38(1):163. PMC: 6463658. DOI: 10.1186/s13046-019-1159-2. View

19.

Yang B, Yao J, Li B, Shao G, Cui Y . Inhibition of protein kinase CK2 sensitizes non-small cell lung cancer cells to cisplatin via upregulation of PML. Mol Cell Biochem. 2017; 436(1-2):87-97. DOI: 10.1007/s11010-017-3081-2. View

20.

Wang X, Zhao B, Roundtree I, Lu Z, Han D, Ma H . N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6):1388-99. PMC: 4825696. DOI: 10.1016/j.cell.2015.05.014. View