STXBP6, reciprocally regulated with autophagy, reduces triple negative breast cancer aggressiveness

Background Although autophagy plays a dual role in suppressing or promoting certain cancers, the nature of its involvement in breast cancers remains unclear. Here, we investigated the function of STXBP6, a protein regulating the autophagy-associated SNARE complex, in triple negative breast cancer (TNBC). Results We report that STXBP6 is profoundly downregulated in TNBC specimens in association with reduced overall patient survival. Notably, we found thatSTXBP6promoter was specifically hyper-methylated in TNBC specimens. Ectopic expression ofSTXBP6inhibited TNBC cell proliferation in cellular and mouse models. Mass spectrometric analysis revealed physical interactions of STXBP6 with a number of autophagy-related proteins including SNX27, a molecule involved in endocytosis of plasma membrane receptors and protein trafficking. Overexpression ofSTXBP6elicited autophagy through inhibition of mTORC1 signaling. Reciprocally, induction of autophagy rescuedSTXBP6expression by inhibiting EZH2 and alteringSTXBP6methylation. The mutual regulation between STXBP6 and autophagy was replicated in luminal breast cancer cells only when estrogen receptor (ER) activation was abrogated. Ectopic expression ofSTXBP6significantly reduced TNBC cells' migratory ability in vitro and tumor metastasis in vivo. Conclusions Our results unveil a role of STXBP6 in TNBC that highlights a new paradigm in autophagy regulation. Our results significantly enhance the understanding of the mechanisms of TNBC aggressiveness, which might help in designing novel therapies targeting TNBC.