SDCBP/Syntenin-1 stabilizes BACH1 by disassembling the SCFFBXO22–BACH1 complex in triple-negative breast cancer

Abstract BACH1 is a redox-sensitive transcription factor facilitating tumor progression in triple-negative breast cancer (TNBC). However, the molecular mechanisms regulating BACH1 function in TNBC remain unclear. In this study, we demonstrate that SDCBP, a tandem-PDZ-domain protein, stabilizes BACH1 by disassembling the Skp1-Cullin1-FBXO22 (SCF FBXO22 )-BACH1 complex via a heme/heme-oxygenase-1-independent manner in TNBC cells. Our data revealed that SDCBP and BACH1 expression show a significant positive correlation in TNBC cells and TNBC patients tumor tissues. Mechanistically, SDCBP via its PDZ1 domain disassembles the SCF FBXO22 –BACH1 complex via its PDZ1 domain, thereby preventing BACH1 K48-linked polyubiquitination and proteasomal degradation. Knocking down SDCBP induces BACH1 degradation and downregulates expressions of BACH1-induced metastatic genes, thereby suppressing tumor progression in mice bearing TNBC tumors. Moreover, depleting SDCBP leads to upregulation of BACH1-repressed electron transport chain (ETC) genes, such as NDUFA4 and COX6B2 , and increases mitochondrial activity, enhancing anti-tumor efficacy of metformin against TNBC both in vitro and in vivo. These data demonstrate a novel alternative mechanism for BACH1 stabilization mediated by SDCBP, implicating the SDCBP-BACH1 axis as a potential target for enhancing ETC inhibitor efficacy in TNBC combinational therapy.