Specific regulation of BACH1 by the hotspot mutant p53R175H reveals a distinct gain-of-function mechanism

Zhenyi Su, Ning Kon, Jingjie Yi, Haiqing Zhao, Wanwei Zhang, Qiaosi Tang, Huan Li, Hiroki Kobayashi, Zhiming Li, Shoufu Duan, Yanqing Liu, Kenneth P. Olive, Zhiguo Zhang, Barry Honig, James J. Manfredi, Anil K. Rustgi, Wei Gu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Although the gain of function (GOF) of p53 mutants is well recognized, it remains unclear whether different p53 mutants share the same cofactors to induce GOFs. In a proteomic screen, we identified BACH1 as a cellular factor that recognizes the p53 DNA-binding domain depending on its mutation status. BACH1 strongly interacts with p53R175H but fails to effectively bind wild-type p53 or other hotspot mutants in vivo for functional regulation. Notably, p53R175H acts as a repressor for ferroptosis by abrogating BACH1-mediated downregulation of SLC7A11 to enhance tumor growth; conversely, p53R175H promotes BACH1-dependent tumor metastasis by upregulating expression of pro-metastatic targets. Mechanistically, p53R175H-mediated bidirectional regulation of BACH1 function is dependent on its ability to recruit the histone demethylase LSD2 to target promoters and differentially modulate transcription. These data demonstrate that BACH1 acts as a unique partner for p53R175H in executing its specific GOFs and suggest that different p53 mutants induce their GOFs through distinct mechanisms.

Original languageEnglish (US)
Pages (from-to)564-581
Number of pages18
JournalNature Cancer
Volume4
Issue number4
DOIs
StatePublished - Apr 2023
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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