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Hum Cell. 2021 Nov 25; doi: 10.1007/s13577-021-00650-9. Epub 2021 Nov 25.

USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer.

Human cell

Zhengliang Li, Xiaojing Liu, Haizhou Yu, Shaoping Wang, Shuliang Zhao, Guoxiang Jiang

Affiliations

  1. Department of Radiotherapy, Yantaishan Hospital, No. 10087 Science and Technology Avenue, Laishan District, Yantai, Shandong, China.
  2. Department of Traditional Chinese Medicine, Yantai Center for Food and Drug Control, Yantai, Shandong, China.
  3. Department of Pharmacology and Toxicology, Yantai Center for Food and Drug Control, Yantai, Shandong, China.
  4. School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China.
  5. Department of Radiotherapy, Yantaishan Hospital, No. 10087 Science and Technology Avenue, Laishan District, Yantai, Shandong, China. [email protected].

PMID: 34825342 DOI: 10.1007/s13577-021-00650-9

Abstract

The ectopic expression of ubiquitin-specific peptidase 21 (USP21) is common in different types of cancer. However, its relationship with radio-sensitivity in cervical cancer (CC) remains unclear. In this study, we aimed to uncover the effect of USP21 on CC radio-resistance and its underlying mechanism. Our results showed that the expression of USP21 was markedly increased in CC tissues of radio-resistant patients and CC cells treated with radiation. Besides, knockdown of USP21 restrained the survival fractions, and facilitated apoptosis of CC cells in the absence or presence of radiation. Additionally, USP21 in combination with FOXM1 regulated the stability and ubiquitination of FOXM1. However, FOXM1 reversed the effects of USP21 knockdown on the radio-resistance of CC cells. Furthermore, FOXM1 knockdown activated the Hippo pathway by inhibiting the nuclear translocation of Yes-associated protein 1 (YAP1), and FOXM1 knockdown attenuated the radio-resistance of CC cells via inhibiting the Hippo-YAP1 pathway. USP21 activated the Hippo pathway by mediating FOXM1. Knockdown of USP21 enhanced the radio-sensitivity of CC cells in vivo. In summary, USP21 contributed to the radio-resistance of CC cells via FOXM1/Hippo signaling, and may serve as a promising target for radio-sensitizers in the radiotherapy of CC.

© 2021. The Author(s) under exclusive licence to Japan Human Cell Society.

Keywords: Cervical cancer; Hippo–YAP1 signaling; Radioresistance; USP21; Ubiquitination

References

  1. Siegel RL, Miller KD. Cancer statistics. CA Cancer J Clin. 2020;70:7–30. - PubMed
  2. Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR. The global burden of women’s cancers: a grand challenge in global health. Lancet (London). 2017;389:847–60. - PubMed
  3. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet (London). 2019;393:169–82. - PubMed
  4. Prosser SL, O’Regan L, Fry AM. Novel insights into the mechanisms of mitotic spindle assembly by NEK kinases. Mol Cell Oncol. 2016;3:1062952. - PubMed
  5. Lopata A, Kniss A, Löhr F. Ubiquitination in the ERAD Process. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21155369 . - PubMed
  6. Yamano K, Kikuchi R, Kojima W, Hayashida R, Koyano F, Kawawaki J. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J Cell Biol. 2020. https://doi.org/10.1083/jcb.201912144 . - PubMed
  7. Das S, Chandrasekaran AP, Suresh B, Haq S, Kang JH, Lee SJ. Genome-scale screening of deubiquitinase subfamily identifies USP3 as a stabilizer of Cdc25A regulating cell cycle in cancer. Cell Death Differ. 2020;27:3004–20. - PubMed
  8. Bonacci T, Emanuele MJ. Dissenting degradation: Deubiquitinases in cell cycle and cancer. Semin Cancer Biol. 2020;67:145–58. - PubMed
  9. Liu J, Kruswick A, Dang H, Tran AD, Kwon SM, Wang XW. Ubiquitin-specific protease 21 stabilizes BRCA2 to control DNA repair and tumor growth. Nat Commun. 2017;8:137. - PubMed
  10. Chen Y, Zhou B, Chen D. USP21 promotes cell proliferation and metastasis through suppressing EZH2 ubiquitination in bladder carcinoma. Onco Targets Ther. 2017;10:681–9. - PubMed
  11. Arceci A, Bonacci T, Wang X, Stewart K, Damrauer JS, Hoadley KA. FOXM1 deubiquitination by usp21 regulates cell cycle progression and paclitaxel sensitivity in basal-like breast cancer. Cell Rep. 2019;26:3076-3086.e6. - PubMed
  12. Xu P, Xiao H, Yang Q, Hu R, Jiang L, Bi R. The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer. Exp Mol Med. 2020;52:41–55. - PubMed
  13. Korver W, Roose J, Clevers H. The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res. 1997;25:1715–9. - PubMed
  14. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59. - PubMed
  15. Liu C, Shi J, Li Q, Li Z, Lou C, Zhao Q. STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer. Clin Sci. 2019;133:645–63. - PubMed
  16. Xiu G, Sui X, Wang Y, Zhang Z. FOXM1 regulates radiosensitivity of lung cancer cell partly by upregulating KIF20A. Eur J Pharmacol. 2018;833:79–85. - PubMed
  17. Li T, Ma J, Han X, Jia Y, Yuan H, Shui S. MicroRNA-320 enhances radiosensitivity of glioma through down-regulation of sirtuin type 1 by directly targeting forkhead box protein M1. Transl Oncol. 2018;11:205–12. - PubMed
  18. Taha Z, Janse van Rensburg HJ, Yang X. The Hippo pathway: immunity and cancer. Cancers. 2018;10:94. - PubMed
  19. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57. - PubMed
  20. Dey A, Varelas X. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat Rev Drug Discov. 2020;19:480–94. - PubMed
  21. Zeng Y, Liu Q, Wang Y, Tian C, Yang Q, Zhao Y. CDK5 activates hippo signaling to confer resistance to radiation therapy via upregulating TAZ in lung cancer. Int J Radiat Oncol Biol Phys. 2020;108:758–69. - PubMed
  22. Zhang S, Zhang X, Sun Q, Zhuang C, Li G, Sun L. LncRNA NR2F2-AS1 promotes tumourigenesis through modulating BMI1 expression by targeting miR-320b in non-small cell lung cancer. J Cell Mol Med. 2019;23:2001–11. - PubMed
  23. Shibata M, Ham K, Hoque MO. A time for YAP1: tumorigenesis, immunosuppression and targeted therapy. Int J Cancer. 2018;143:2133–44. - PubMed
  24. Chang Y, Fu XR, Cui M, Li WM, Zhang L, Li X. Activated hippo signal pathway inhibits cell proliferation and promotes apoptosis in NK/T cell lymphoma cells. Cancer Med. 2019;8:3892–904. - PubMed
  25. Luo J, Yu FX. GPCR-hippo signaling in cancer. Cells. 2019;8:426. - PubMed
  26. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15:642–56. - PubMed
  27. Sun HL, Men JR, Liu HY, Liu MY, Zhang HS. FOXM1 facilitates breast cancer cell stemness and migration in YAP1-dependent manner. Arch Biochem Biophys. 2020;685:108349. - PubMed
  28. Peng L, Hu Y, Chen D, Jiao S, Sun S. Ubiquitin specific peptidase 21 regulates interleukin-8 expression, stem-cell like property of human renal cell carcinoma. Oncotarget. 2016;7:42007–16. - PubMed
  29. Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem. 2017;86:159–92. - PubMed
  30. Chen Y, Li Y, Xue J, Gong A, Yu G, Zhou A. Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation. EMBO J. 2016;35:668–84. - PubMed
  31. Yue M, Li S, Yan G, Li C, Kang Z. Paeoniflorin inhibits cell growth and induces cell cycle arrest through inhibition of FoxM1 in colorectal cancer cells. Cell Cycle (Georgetown). 2018;17:240–9. - PubMed
  32. Nakamura S, Hirano I, Okinaka K, Takemura T, Yokota D, Ono T. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis. 2010;31:2012–21. - PubMed
  33. Varghese V, Magnani L. FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression. Sci Rep. 2019;9:1505. - PubMed
  34. Peng WX, Han X, Zhang CL, Ge L, Du FY, Jin J. FoxM1-mediated RFC5 expression promotes temozolomide resistance. Cell Biol Toxicol. 2017;33:527–37. - PubMed
  35. Nguyen HT, Hong X, Tan S, Chen Q, Chan L, Fivaz M. Viral small T oncoproteins transform cells by alleviating hippo-pathway-mediated inhibition of the YAP proto-oncogene. Cell Rep. 2014;8:707–13. - PubMed
  36. Kim W, Khan SK, Liu Y, Xu R, Park O, He Y. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut. 2018;67:1692–703. - PubMed
  37. Byrne JJ, Soh MS, Chandhok G, Vijayaraghavan T, Teoh JS, Crawford S. Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans. Cell Mol Life. 2019;76:1967–85. - PubMed
  38. Tocci P, Cianfrocca R, Di Castro V, Rosanò L, Sacconi A, Donzelli S. β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer. Nat Commun. 2019;10:3196. - PubMed
  39. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006;103:12405–10. - PubMed
  40. Fullenkamp CA, Hall SL, Jaber OI, Pakalniskis BL, Savage EC, Savage JM. TAZ and YAP are frequently activated oncoproteins in sarcomas. Oncotarget. 2016;7:30094–108. - PubMed
  41. Bae SJ, Kim M, Kim SH, Kwon YE, Lee JH, Kim J. NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway. Nat Commun. 2015;6:6314. - PubMed
  42. Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 2010;24:72–85. - PubMed
  43. Liu CY, Zha ZY, Zhou X, Zhang H, Huang W, Zhao D. The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem. 2010;285:37159–69. - PubMed
  44. Hong X, Nguyen HT, Chen Q, Zhang R, Hagman Z, Voorhoeve PM. Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover. EMBO J. 2014;33:2447–57. - PubMed
  45. Nguyen HT, Kugler JM, Loya AC, Cohen SM. USP21 regulates Hippo pathway activity by mediating MARK protein turnover. Oncotarget. 2017;8:64095–105. - PubMed

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