Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth

FASEB J. 2019 Nov;33(11):12112-12123. doi: 10.1096/fj.201900499RR. Epub 2019 Aug 2.


Because bladder cancer (BC) is one of the most common malignant cancers of the urinary system, identification of BC cell growth-associated effectors is of great significance. Cyclin-dependent kinase (CDK)6 is a member of the CDK family of cell cycle-related proteins and plays an important role in cancer cell growth. This is borne out by the fact that a CDK6 inhibitor had been approved to treat several types of cancers. Nevertheless, underlying molecular mechanisms concerning how to regulate CDK6 expression in BC remains unclear. In the present study, it was observed that miR-934 was much higher in human BCs and human BC cell lines as well. The results also revealed that miR-934 inhibition dramatically decreased human BC cell monolayer growth in vitro and xenograft tumor growth in vivo; the outcomes were accompanied by CDK6 protein down-regulation and G0-G1 cell cycle arrest. Moreover, overexpression of CDK6 reversed the inhibition of BC cell growth induced by miR-934. Further studies showed that miR-934 binds to a 3'-UTR of ubiquitin-conjugating enzyme 2N (ube2n) mRNA, down-regulated UBE2N protein expression; this, in turn, attenuated CDK6 protein degradation and led to CDK6 protein accumulation as well as the promotion of BC tumor growth. Collectively, this study not only establishes a novel regulatory axis of miR-934/UBE2N of CDK6 but also provides data suggesting that miR-934 and UBE2N may be potentially promising targets for therapeutic strategies against BC.-Yan, H., Ren, S., Lin, Q., Yu, Y., Chen, C., Hua, X., Jin, H., Lu, Y., Zhang, H., Xie, Q., Huang, C., Huang, H. Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth.

Keywords: 3’-UTR; cell cycle; proliferation; tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Cyclin-Dependent Kinase 6 / genetics*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Nude
  • MicroRNAs / genetics*
  • Proteolysis
  • RNA Interference
  • RNAi Therapeutics / methods
  • Ubiquitin-Conjugating Enzymes / genetics*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Xenograft Model Antitumor Assays / methods


  • 3' Untranslated Regions
  • MIRN934 microRNA, human
  • MicroRNAs
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • Cyclin-Dependent Kinase 6