# TRIM38 Suppresses Breast Cancer Progression via Modulating SQSTM1 Ubiquitination and Autophagic Flux

## TL;DR

TRIM38, a protein involved in ubiquitination, suppresses breast cancer progression by blocking autophagy and is linked to better patient outcomes.

## Contribution

TRIM38 is identified as a novel regulator of autophagy through K63-linked ubiquitination of SQSTM1/p62 in breast cancer.

## Key findings

- TRIM38 is downregulated in breast cancer tissues and correlates with poor clinical outcomes.
- TRIM38 inhibits breast cancer proliferation, migration, and invasion in vitro and in vivo.
- TRIM38 promotes K63-linked ubiquitination of SQSTM1 at K420, disrupting autophagic flux.

## Abstract

TRIM38, an E3 ubiquitin‐protein ligase, has previously been implicated in innate immune and inflammatory responses, yet its role in breast cancer regulation remains unclear. This study elucidates the suppressive function of TRIM38 in breast cancer progression. The results indicate a decreased expression of TRIM38 in breast cancer tissues compared to adjacent non‐cancerous counterparts, and its reduced expression correlates with unfavorable clinical outcomes in breast cancer patients. Both in vitro and in vivo experiments demonstrate that TRIM38 inhibits breast cancer proliferation, migration, and invasion. Furthermore, an inverse regulatory relationship between TRIM38 protein level and autophagic flux is observed. Mechanistically, SQSTM1/p62 is identified as a novel substrate of TRIM38, which promotes non‐degradative K63‐linked ubiquitination at SQSTM1 K420 residue. This kind of ubiquitination disrupts the interaction between SQSTM1 and LC3, thereby impeding autophagic flux. Collectively, the findings underscore TRIM38 as a crucial regulator of autophagy and present novel, promising therapeutic targets for breast cancer.

TRIM38, an E3 ubiquitin ligase, suppresses breast cancer progression by inhibiting proliferation, migration, and invasion. Downregulated in breast tumor, its loss correlates with poor prognosis. Mechanistically, TRIM38 mediates K63‐linked ubiquitination of SQSTM1/p62 at K420, disrupting SQSTM1‐LC3 interaction and blocking autophagic flux. These findings highlight TRIM38 as a key autophagy regulator and a potential therapeutic target.