Phosphorylation-dependent deubiquitinase OTUD3 regulates YY1 stability and promotes colorectal cancer progression

Liang Wu; Zili Zhou; Yang Yu; Can Cheng; Shuai Zhou; Yuan Yan; Bofan Yu; Yuwei Zhang; Zhengyi Liu

doi:10.1038/s41419-024-06526-8

Phosphorylation-dependent deubiquitinase OTUD3 regulates YY1 stability and promotes colorectal cancer progression

Cell Death Dis. 2024 Feb 13;15(2):137. doi: 10.1038/s41419-024-06526-8.

Authors

Liang Wu^#¹, Zili Zhou^#², Yang Yu^#^{3

4}, Can Cheng¹, Shuai Zhou⁵, Yuan Yan³, Bofan Yu³, Yuwei Zhang⁶, Zhengyi Liu⁷

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, 230001, China.
² Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, Sichuan, China.
³ Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China.
⁴ Microbiome Laboratory, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.
⁵ Translational Research Institute, Henan Provincial and Zhengzhou City Key Laboratory of Non-coding RNA and Cancer Metabolism, Henan International Join Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁶ Key Laboratory of Stem Cell Differentiation & Modification, School of Clinical Medicine, Henan University, Zhengzhou, 450000, China.
⁷ Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China. zhengyiliu159@126.com.

^# Contributed equally.

Abstract

Yin Yang 1 (YY1) is a key transcription factor that has been implicated in the development of several malignancies. The stability of YY1 is regulated by the ubiquitin-proteasome system. The role of deubiquitinases (DUBs) and their impact on YY1 remain to be fully elucidated. In this study, we screened for ubiquitin-specific proteases that interact with YY1, and identified OTUD3 as a DUB for YY1. Over-expressed OTUD3 inhibited YY1 degradation, thereby increasing YY1 protein levels, whereas OTUD3 knockdown or knockout promoted YY1 degradation, thereby decreasing the proliferation of colorectal cancer (CRC). Furthermore, PLK1 mediates OTUD3 S326 phosphorylation, which further enhances OTUD3 binding and deubiquitination of YY1. In CRC tissues, elevated the expression level of OTUD3 and YY1 were significantly associated with poor prognostic outcomes. These findings suggest that the OTUD3-YY1 pathway has therapeutic potential in CRC, and OTUD3 plays a critical role in regulating YY1.

MeSH terms

Colorectal Neoplasms* / genetics
Humans
Phosphorylation
Ubiquitin / metabolism
Ubiquitin-Specific Proteases* / metabolism
YY1 Transcription Factor / metabolism

Substances

Ubiquitin-Specific Proteases
YY1 Transcription Factor
Ubiquitin
YY1 protein, human
OTUD3 protein, human