# WWP2-induced inhibition of hepatocellular carcinoma cellular senescence via the ubiquitination and degradation of p21

## TL;DR

This study shows how the protein WWP2 promotes liver cancer by breaking down p21, and how CMTM6 can counteract this process.

## Contribution

The discovery of WWP2 as an E3 ubiquitin ligase for p21 and its interaction with CMTM6 in regulating HCC senescence is novel.

## Key findings

- WWP2 promotes p21 degradation via ubiquitination, accelerating HCC progression.
- CMTM6 stabilizes p21 by inhibiting WWP2-mediated ubiquitination.
- WWP2 depletion and CMTM6 overexpression synergistically suppress HCC tumor growth in vivo.

## Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. The E3 ubiquitin ligase WWP2 has emerged as a critical regulator of tumor pathogenesis through its modulation of substrate ubiquitination. However, its specific mechanistic role in HCC remains poorly understood. In this study, we found that WWP2 was significantly up-regulated in HCC patients and associated with poor prognosis. Lentivirus-mediated knockdown of WWP2 induced cellular senescence and suppressed proliferation in HCC cell lines. Mechanistically, co-immunoprecipitation and ubiquitination assays identified WWP2 as a novel E3 ubiquitin ligase for p21 that promotes its K48-linked ubiquitination and subsequent proteasomal degradation, consequently accelerating cellular senescence and restraining HCC progression. Notably, we further discovered that CMTM6 directly interacts with WWP2, thereby stabilizing p21 by preventing its WWP2-mediated ubiquitination. Accordingly, the senescence and proliferation arrest induced by WWP2 deficiency were partially reversed by CMTM6 knockdown but enhanced by concurrent CMTM6 overexpression. This functional interplay was corroborated in vivo, as WWP2 depletion enhanced tumor cell senescence and suppressed tumor growth, an effect that was partially rescued by concurrent CMTM6 knockdown. Taken together, our findings establish the WWP2–CMTM6–p21 axis as a pivotal regulatory mechanism of cellular senescence in HCC and shed new light on senescence-related therapeutic strategies for HCC.