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

Su et al. find that BACH1 specifically interacts with the p53 (R175H) hotspot mutant. This has double oncogenic effects, leading to increased expression of the pro-metastatic targets of BACH1 as well as blockage of its capacity to activate ferroptosis. 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 p53(R175H) but fails to effectively bind wild-type p53 or other hotspot mutants in vivo for functional regulation. Notably, p53(R175H) acts as a repressor for ferroptosis by abrogating BACH1-mediated downregulation of SLC7A11 to enhance tumor growth; conversely, p53(R175H) promotes BACH1-dependent tumor metastasis by upregulating expression of pro-metastatic targets. Mechanistically, p53(R175H)-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 p53(R175H) in executing its specific GOFs and suggest that different p53 mutants induce their GOFs through distinct mechanisms.