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

Bo Yu, Fei Luo, Bowen Sun, Wenxue Liu, Qiqi Shi, Shi Yuan Cheng, Ceshi Chen, Guoqiang Chen, Yanxin Li, Haizhong Feng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalAdvanced Science
DOIs
StateAccepted/In press - 2021

Keywords

  • KAT6A
  • SMAD3
  • immunotherapy
  • metastasis
  • myeloid-derived suppressor cells
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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