TRIM22 induces cellular senescence by targeting PHLPP2 in hepatocellular carcinoma

Donghee Kang, Hyun Jung Hwang, Yurim Baek, Jee Young Sung, Kyeong Jin Kim, Heon Joo Park, Young Gyu Ko, Yong Nyun Kim, Jae Seon Lee

Research output: Contribution to journalArticlepeer-review

Abstract

The ubiquitin-proteasome system is a vital protein degradation system that is involved in various cellular processes, such as cell cycle progression, apoptosis, and differentiation. Dysregulation of this system has been implicated in numerous diseases, including cancer, vascular disease, and neurodegenerative disorders. Induction of cellular senescence in hepatocellular carcinoma (HCC) is a potential anticancer strategy, but the precise role of the ubiquitin-proteasome system in cellular senescence remains unclear. In this study, we show that the E3 ubiquitin ligase, TRIM22, plays a critical role in the cellular senescence of HCC cells. TRIM22 expression is transcriptionally upregulated by p53 in HCC cells experiencing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, the SPRY domain of TRIM22 directly associates with the C-terminal domain of PHLPP2, which contains phosphorylation sites that are subject to IKKβ-mediated phosphorylation. The TRIM22-mediated PHLPP2 degradation leads to activation of AKT-p53-p21 signaling, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, the levels of TRIM22 and PHLPP2 show inverse correlations at the mRNA and protein levels. Collectively, our findings reveal that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, suggesting that TRIM22 could potentially serve as a therapeutic target for treating cancer.

Original languageEnglish
Article number26
JournalCell Death and Disease
Volume15
Issue number1
DOIs
Publication statusPublished - 2024 Jan

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'TRIM22 induces cellular senescence by targeting PHLPP2 in hepatocellular carcinoma'. Together they form a unique fingerprint.

Cite this