KAT6A Acetylation of SMAD3 Regulates Myeloid-Derived Suppressor Cell Recruitment, Metastasis, and Immunotherapy in Triple-Negative Breast Cancer.

Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis, yet the underlying mechanisms are still elusive. Here, SMAD3 is identified as a nonhistone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A promotes SMAD3 association with oncogenic chromatin modifier ...
tripartite motif-containing 24 (TRIM24) and disrupts SMAD3 interaction with tumor suppressor TRIM33. This event in turn promotes KAT6A-acetylated H3K23-mediated recruitment of TRIM24-SMAD3 complex to chromatin and thereby increases SMAD3 activation and immune response-related cytokine expression, leading to enhanced breast cancer stem-like cell stemness, myeloid-derived suppressor cell (MDSC) recruitment, and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating TNBC xenograft-bearing animals markedly attenuates metastasis and provides a significant survival benefit. Thus, the work presents a KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the antimetastasis efficacy.
Mesh Terms:
Acetylation, Animals, B7-H1 Antigen, Carrier Proteins, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Heterografts, Histone Acetyltransferases, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Mice, Myeloid-Derived Suppressor Cells, Neoplasm Metastasis, Smad3 Protein, Transcription Factors, Triple Negative Breast Neoplasms
Adv Sci (Weinh)
Date: Dec. 01, 2020
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