Int J Biol Sci 2022; 18(8):3528-3543. doi:10.7150/ijbs.72629 This issue Cite

Research Paper

UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

Shengmeng Peng1,2#, Xu Chen1,2#, Chaoyun Huang3#, Chenwei Yang1,2, Minyi Situ4, Qianghua Zhou1,2, Yihong Ling3, Hao Huang1,2, Ming Huang1,2, Yangjie Zhang1,2, Liang Cheng1,2, Qiang Zhang1,2, Zhenghui Guo1,2✉, Yiming Lai1,2✉, Jian Huang1,2,5✉

1. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P. R. China.
2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China.
3. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
4. Department of Animal Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
5. Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, P. R. China.
#These authors contributed equally to this work.

Citation:
Peng S, Chen X, Huang C, Yang C, Situ M, Zhou Q, Ling Y, Huang H, Huang M, Zhang Y, Cheng L, Zhang Q, Guo Z, Lai Y, Huang J. UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer. Int J Biol Sci 2022; 18(8):3528-3543. doi:10.7150/ijbs.72629. https://www.ijbs.com/v18p3528.htm
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Abstract

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Bone metastasis is the main site of metastasis and causes the most deaths in patients with prostate cancer (PCa). The mechanism of bone metastasis is complex and not fully clarified. By RNA sequencing and analysing key pathways in bone metastases of PCa, we found that one of the most important characteristics during PCa bone metastasis was G1/S transition acceleration caused by low protein levels of p16INK4a (p16). Interestingly, we demonstrated that UBE2S bound and degraded p16 through K11- rather than K48- or K63-linked ubiquitination, which accelerated PCa tumour cell G1/S transition in vivo and in vitro. Moreover, UBE2S also stabilized β-catenin through K11-linked ubiquitination, leading to enhanced migration and invasion of tumour cells in PCa bone metastasis. Based on our cohorts and public databases, UBE2S was overexpressed in bone metastases and positively correlated with a high Gleason score, advanced nodal metastasis status and poor prognosis in PCa. Finally, targeting UBE2S with cephalomannine inhibited proliferation and invasion in vitro, and bone metastasis of PCa in vivo. This study innovatively discovered that UBE2S plays an oncogenic role in bone metastasis of PCa by degrading p16 and stabilizing β-catenin via K11-linked ubiquitination, suggesting that it may serve as a multipotent target for metastatic PCa treatment.

Keywords: UBE2S, Bone metastasis of PCa, p16, β-catenin, K11-linked ubiquitination


Citation styles

APA
Peng, S., Chen, X., Huang, C., Yang, C., Situ, M., Zhou, Q., Ling, Y., Huang, H., Huang, M., Zhang, Y., Cheng, L., Zhang, Q., Guo, Z., Lai, Y., Huang, J. (2022). UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer. International Journal of Biological Sciences, 18(8), 3528-3543. https://doi.org/10.7150/ijbs.72629.

ACS
Peng, S.; Chen, X.; Huang, C.; Yang, C.; Situ, M.; Zhou, Q.; Ling, Y.; Huang, H.; Huang, M.; Zhang, Y.; Cheng, L.; Zhang, Q.; Guo, Z.; Lai, Y.; Huang, J. UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer. Int. J. Biol. Sci. 2022, 18 (8), 3528-3543. DOI: 10.7150/ijbs.72629.

NLM
Peng S, Chen X, Huang C, Yang C, Situ M, Zhou Q, Ling Y, Huang H, Huang M, Zhang Y, Cheng L, Zhang Q, Guo Z, Lai Y, Huang J. UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer. Int J Biol Sci 2022; 18(8):3528-3543. doi:10.7150/ijbs.72629. https://www.ijbs.com/v18p3528.htm

CSE
Peng S, Chen X, Huang C, Yang C, Situ M, Zhou Q, Ling Y, Huang H, Huang M, Zhang Y, Cheng L, Zhang Q, Guo Z, Lai Y, Huang J. 2022. UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer. Int J Biol Sci. 18(8):3528-3543.

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