ZRANB1 and ACSS2 Cooperate to Regulate Ubiquitination and Acetylation to Stabilize TWIST1 in Breast Cancer Metastasis

The epithelial-mesenchymal transition (EMT) transcription factor TWIST1 plays a critical role in breast cancer progression. This study reveals that TWIST1 acetylation, which is elevated in metastatic breast cancer tissues, is regulated by a deubiquitination-acetylation crosstalk. We demonstrate that ZRANB1 binds to and deubiquitinates TWIST1, thereby increasing its protein stability. This stabilization enhances the interaction between TWIST1 and the acetyltransferase ACSS2, leading to further TWIST1 acetylation. ACSS2 overexpression reversed ZRANB1 knockdown-induced inhibition of TWIST1 acetylation. Functionally, ZRANB1 overexpression promoted breast cancer cell proliferation, invasion, migration, and EMT in vitro, as well as lung metastasis in vivo, all of which were reversed by ACSS2 knockdown. Conversely, ACSS2 knockdown suppressed TWIST1 acetylation, EMT, and metastatic capabilities. Consistently, ACSS2 overexpression rescued the inhibitory effects of ZRANB1 knockdown on breast cancer cell viability, proliferation, migration, and invasion. In summary, our findings identify a novel regulatory axis wherein ZRANB1-mediated deubiquitination facilitates ACSS2-dependent acetylation to stabilize TWIST1, thereby driving EMT and metastasis in breast cancer. The ZRANB1/ACSS2 axis presents a promising therapeutic target for combating metastasis.