期刊
BIOCHEMICAL JOURNAL
卷 477, 期 1, 页码 137-160出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20190596
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资金
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-03687]
- Diabetes Canada [NOD_OG-3-15-5037-TP, NOD_SC-5-16-5054-TP]
- Beatrice Hunter Cancer Research Institute
- New Brunswick Health Research Foundation
- Terry Fox Research Institute (TFRI)
- Canadian Breast Cancer Foundation - Atlantic Region
- NSERC
- Dalhousie Medicine New Brunswick
Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy with critical roles in several cancers. Lysosomal autophagy promotes cancer survival through the degradation of toxic molecules and the maintenance of adequate nutrient supply. Doxorubicin (DOX) is the standard of care treatment for triple-negative breast cancer (TNBC); however, chemoresistance at lower doses and toxicity at higher doses limit its usefulness. By targeting pathways of survival, DOX can become an effective antitumor agent. In this study, we examined the role of TFEB in TNBC and its relationship with autophagy and DNA damage induced by DOX. In TNBC cells, TFEB was hypophosphorylated and localized to the nucleus upon DOX treatment. TFEB knockdown decreased the viability of TNBC cells while increasing caspase-3 dependent apoptosis. Additionally, inhibition of the TFEB-phosphatase calcineurin sensitized cells to DOX-induced apoptosis in a TFEB dependent fashion. Regulation of apoptosis by TFEB was not a consequence of altered lysosomal function, as TFEB continued to protect against apoptosis in the presence of lysosomal inhibitors. RNA-Seq analysis of MDA-MB-231 cells with TFEB silencing identified a down-regulation in cell cycle and homologous recombination genes while interferon-gamma and death receptor signaling genes were up-regulated. In consequence, TFEB knockdown disrupted DNA repair following DOX, as evidenced by persistent gamma H2A.X detection. Together, these findings describe in TNBC a novel lysosomal independent function for TFEB in responding to DNA damage.
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