RNF125 mediates the anti-breast cancer activity of betulinic acid through ubiquitin-dependent degradation of MYH9.

Authors

Peng Zhang, Yuan Chang, Xiaolu Yang, Binglu He, Li Ma

Published in

International journal of clinical oncology. Jun 18, 2026. Epub Jun 18, 2026.

Abstract

Breast cancer (BC) represents one of the leading causes of cancer-related mortality in women worldwide. Betulinic acid (BA), a naturally derived pentacyclic triterpenoid, exhibits anti-BC activity. Recent evidence implicates RNF125, a RING-domain E3 ubiquitin ligase, as a tumor suppressor. This study aimed to elucidate whether BA exerts anti-BC effects via RNF125 regulation and explored the underlying mechanisms.
RNF125-overexpressing or knockdown BC cell lines were generated to examine the regulatory effect on cell proliferation, motility, and invasiveness. Furthermore, a subcutaneous xenograft mouse model was established to evaluate the influence of RNF125 on tumor growth in vivo.
Bioinformatics analyses revealed BA-mediated upregulation of RNF125 in BC cells. Pan-cancer data indicated reduced RNF125 expression in BC specimens, correlating with unfavorable survival outcomes. Consistently, our results showed that BA upregulates RNF125 protein expression in a concentration-dependent manner. In clinically collected BC samples, diminished RNF125 expression was significantly associated with advanced TNM staging. Functional assays demonstrated that RNF125 overexpression suppressed cell proliferation, migration, and invasion. Conversely, RNF125 knockdown reversed these effects and abrogated BA-mediated suppression of malignant phenotypes in BC cells. Mechanistically, RNF125 interacted with MYH9 (Myosin Heavy Chain 9) to facilitate its ubiquitin-mediated proteasomal degradation. In BA-treated BC cells, the protein expression of MYH9 was inhibited. Ectopic MYH9 expression reversed the tumor-suppressive effects of RNF125 overexpression. Finally, a murine xenograft model confirmed that RNF125 overexpression inhibits BC tumor growth.
These findings suggested that RNF125 mediates the anti-tumor effect of BA, at least in part, through ubiquitin-dependent degradation of MYH9.

PMID:
42315734
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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