GSE171230
KAT6A acetylation of SMAD3 regulates  tumor metastasis in triple-negative breast cancer
Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis. However, the drivers of SMAD3 activation are poorly defined. Here, we identify SMAD3 as a non-histone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A with promotes SMAD3 association with oncogenic H3K23ac reader TRIM24 and upregulation of immune response-related cytokines. This event in turn leads to enhanced myeloid-derived suppressor cell (MDSC) recruitment and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating breast cancer xenograft-bearing animals markedly attenuates TNBC metastasis and provides a significant survival benefit. Thus, our work presents an KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the anti-metastasis efficacy. Overall design: Examination of differential gene expression in MDA-MB-231 cells transducted with SMAD3 wild type (WT) or the K20/117Q  (2KQ) mutant