2. Academic Validation
  3. RSK2-mediated phosphorylation and degradation of UBE2O inhibits hepatocellular carcinoma growth and resistance to radiotherapy

RSK2-mediated phosphorylation and degradation of UBE2O inhibits hepatocellular carcinoma growth and resistance to radiotherapy

  • Cancer Lett. 2025 Apr 10:615:217558. doi: 10.1016/j.canlet.2025.217558.
Yumei Huang 1,  Anchen Qiu 2,  Yimei Meng 2,  Ming Lin 2,  Yunhong Xu 3,  Liu Yang 4
Affiliations

Affiliations

  • 1 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Zhejiang Province Key Disciplines in Traditional Chinese Medicine-Integrated Traditional Chinese and Western Medicine Clinical Oncology, Hangzhou, Zhejiang, 310014, China. Electronic address: huangyumei@hmc.edu.cn.
  • 2 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 3 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: hust_2024_xyh@hust.edu.cn.
  • 4 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Zhejiang Province Key Disciplines in Traditional Chinese Medicine-Integrated Traditional Chinese and Western Medicine Clinical Oncology, Hangzhou, Zhejiang, 310014, China. Electronic address: yangliu@hmc.edu.cn.
PMID: 39954933 DOI: 10.1016/j.canlet.2025.217558
Abstract

Radioresistance poses the main challenge in radiation therapy (RT) for liver Cancer, with the DNA Damage response (DDR) being a crucial component of this resistance. Ubiquitin-conjugating Enzyme E2O (UBE2O) has been implicated in regulating tumor proliferation, Cholesterol metabolism, and drug resistance. However, the role of the ubiquitin-conjugating Enzyme E2O (UBE2O) in DDR of liver Cancer remains to be fully explored. We discovered an elevated expression of UBE2O within liver Cancer tissues, which was notably associated with unfavorable prognoses in hepatocellular carcinoma (HCC) patients. Furthermore, we found that the suppression of UBE2O can effectively reduce the growth and resistance to radiotherapy of HCC cells in vitro and in vivo. Moreover, p90 ribosomal S6 kinase2 (RSK2) was confirmed as a novel interacting kinase of UBE2O, which mediated the phosphorylation and degradation of UBE2O at the Thr838 site. RSK2 inhibition promotes tumor proliferation and resistance to radiotherapy of HCC cells in vitro and in vivo, and these effects are abrogated upon UBE2O knockdown. Collectively, our work revealed that UBE2O promotes tumor progression and resistance to radiotherapy, which was negatively regulated by RSK2 for phosphorylation and degradation, indicating that the RSK2/UBE2O axis provides a potential radiosensitization target for HCC patients.

Keywords

HCC; Phosphorylation; RSK2; Radioresistance; UBE2O.

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