Open AccessSTXBP6, reciprocally regulated with autophagy, reduces triple negative breast cancer aggressiveness
Author(s) -
Lenka Govinda,
Shan Jingxuan,
Halabi Najeeb,
Abuaqel Sirin W J,
Goswami Neha,
Schmidt Frank,
Zaghlool Shaza,
Romero Atilio Reyes,
Subramanian Murugan,
Boujassoum Salha,
AlBozom Issam,
Gehani Salah,
Khori Noor Al,
Bedognetti Davide,
Suhre Karsten,
Ma Xiaojing,
Dömling Alexander,
Rafii Arash,
Chouchane Lotfi
Publication year - 2020
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.147
Subject(s) - autophagy , triple negative breast cancer , ectopic expression , cancer research , breast cancer , biology , microbiology and biotechnology , cancer , medicine , apoptosis , cell culture , genetics , biochemistry
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.