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

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.

GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

“…Yin Yang‐1 (YY1) is a widely expressed zinc finger transcription factor that exerts significant regulatory control over gene transcription in various cellular processes, encompassing cell proliferation, differentiation and tumorigenesis. 18 , 19 As a multifunctional protein, YY1 was previously shown to have dual roles in gene activation and repression depending on the cellular context, 20 and it may be involved in the transcriptional regulation of 10% of the total mammalian gene set. 21 Physiologically, YY1 is found to be overexpressed in several malignancies, including prostate cancer, 22 colon cancer, 23 metastatic breast cancer 24 and gastric cancer.…”