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

Adv Sci (Weinh). 2021 Oct;8(20):e2100014. doi: 10.1002/advs.202100014. Epub 2021 Aug 13.

Abstract

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.

Keywords: KAT6A; SMAD3; immunotherapy; metastasis; myeloid-derived suppressor cells; triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • Carrier Proteins / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Histone Acetyltransferases / genetics*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunotherapy / methods
  • Mice
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / metabolism
  • Neoplasm Metastasis
  • Smad3 Protein / genetics*
  • Transcription Factors / genetics*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Carrier Proteins
  • Immune Checkpoint Inhibitors
  • SMAD3 protein, human
  • Smad3 Protein
  • TRIM24 protein, human
  • TRIM33 protein, human
  • Transcription Factors
  • Histone Acetyltransferases
  • KAT6A protein, human