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

Abstract

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 that STXBP6 promoter was specifically hyper‐methylated in TNBC specimens. Ectopic expression of STXBP6 inhibited 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 of STXBP6 elicited autophagy through inhibition of mTORC1 signaling. Reciprocally, induction of autophagy rescued STXBP6 expression by inhibiting EZH2 and altering STXBP6 methylation. The mutual regulation between STXBP6 and autophagy was replicated in luminal breast cancer cells only when estrogen receptor (ER) activation was abrogated. Ectopic expression of STXBP6 significantly 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.

Macrophage fusion event as one prerequisite for inorganic nanoparticle-induced antitumor response

“…We then examined the function of STXBP6 in modulating cellular events. In the literature, STXBP6 is identified as a regulator of autophagosome formation ( 41 , 42 ). In our microarray analysis, we also found that the genes involved in various stages of autophagosome formation were preferentially up-regulated by the antitumor nanoparticles (fig.…”

“…However, how STXBP6 is involved in regulating MNGC generation is still unknown. Other research groups have demonstrated that STXBP6 is a regulator of autophagosome formation (41,42). We then tried to explore the role of autophagy in antitumor nanoparticle-induced MNGC formation.…”

Genome-Wide Association Study for Udder Conformation Traits in Chinese Holstein Cattle

“…The STXBP6 gene provides a syntoxin-binding protein which attaches to the SNARE complex components, preventing membrane fusions such as phagocytosis [ 59 ], and the STXBP6 gene causes rheumatoid arthritis [ 60 ]. It has also been expressed in the breast cancer cells of mice [ 61 ]. The SLF1 gene is also important in genome stability maintenance in human cells after DNA damage [ 62 ].…”