A lysosome independent role for TFEB in activating DNA repair and inhibiting apoptosis in breast cancer cells

Abstract

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 hypo-phosphorylated 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-γ and death receptor signaling genes were up-regulated. In consequence, TFEB knockdown disrupted DNA repair following DOX, as evidenced by persistent γH2A.X detection. Together, these findings describe in TNBC a novel lysosomal independent function for TFEB in responding to DNA damage.

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

“…Previous studies showed that proinflammatory cytokines and ceramides induce apoptosis (36). Our functional analyses of DEGs in EP highlighted the enrichment in the MF group of apoptosis-associated systems such as protein ubiquitination, ATM, ceramide, death receptor signaling, and NER pathways (37)(38)(39)(40)(41)(42). In further support of our results, a recent in vitro study showed that human milk reduced cellular apoptosis in intestinal epithelial cells through the inhibition of oxidative stress (43).…”

TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response

“…Several genotoxic stressors inducing DDR such as etoposide, cisplatin, UVC, and doxorubicin can induce TFEB nuclear translocation [26,45]. Indeed, we found that TFEB activation is essential to induce p21 up-regulation upon treatment with the DNA-damage agent doxorubicin.…”

Exosomal LncRNA–NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p

“…NEAT1 is important for gene stability [44]. A previous study showed that Dox promoted cellular damage though impairing gene stability [45]. Moreover, silencing lncRNA-NEAT1 in MSCs, even MSCs treated with MIF, could not exert a cardioprotective effect, with shortened telomere length and impaired telomerase activity, both important in gene stability [46].…”