TRIM35, a novel DNA-binding protein, epigenetically modifies H3 to promote HSPA6 transcription and suppress breast cancer progression

Tripartite Motif Containing 35 (TRIM35) is a well-characterized ubiquitin ligase with established roles in antiviral immunity, cancer metabolism, cardiovascular function, and tumor progression. However, its function as a DNA-binding protein has not been previously explored. In this study, we provide the first evidence that TRIM35 directly binds genomic promoters, thereby identifying it as a novel regulator of gene transcription. This finding opens new avenues for understanding the biological functions of TRIM35, expanding its potential role in cellular regulation. Furthermore, our results show that TRIM35 interacts with histone H3 (H3) and catalyzes its non-proteolytic ubiquitination, which serves as a recruitment signal for p300, leading to subsequent H3K27 acetylation and activation of gene transcription. Notably, among the genes regulated, Heat Shock Protein Family A (Hsp70) Member 6 (HSPA6) is significantly upregulated through TRIM35-mediated transcriptional regulation, which suppresses breast cancer progression and mediates TRIM35’s anti-tumor effect. Collectively, our findings reveal a previously unrecognized mechanism by which TRIM35 regulates gene expression through targeted epigenetic modification, providing new insights into its tumor-suppressive role in breast cancer.