Abstract
Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAFV600E-melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAFV600E via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the “BRAF-TFEB-autophagy-lysosome” axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.
Highlights
Autophagy maintains homeostasis and is induced upon stress
ZKSCAN3 depletion synergized with transcription factor EB (TFEB) overexpression and resulted in growth inhibition of A375 xenograft melanoma (Supplementary Fig. 5f–h). These results indicate that TFEB/ ZKSCAN3-dependent regulation of the autophagy–lysosomal pathway suppresses BRAFV600E melanoma progression
Melanocytes do not belong to the epithelial lineage, E-cadherin is required for melanocyte differentiation and suppresses their proliferation; loss of E-cadherin is associated with tumor progression and metastasis of melanoma[33]. These results indicate that TFEB S142 phosphorylation and the resultant suppression of autophagy–lysosomal transcription serve as downstream effectors of BRAFV600E, contributing to tumor progression and poor differentiation
Summary
Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. We show that in BRAFV600E-melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. Starvation/lysosomal stress releases mTORC1 from the lysosome, and nonphosphorylated TFEB/TFE3 translocate to the nucleus and induces expression of autophagy–lysosome-relevant genes[8,12]. Zinc finger with KRAB and SCAN domains 3 (ZKSCAN3)[13], a transcriptional repressor of the autophagy–lysosome network, is regulated in conjunction with TFEB during starvation/lysosome activation through c-Jun N-terminal kinase 2/p38 mitogen-activated protein kinase (JNK2/p38 MAPK)-mediated phosphorylation[14]. Constitutive TFEB phosphorylation by the BRAFV600E downstream effector ERK leads to its cytoplasmic retention and impaired expression of autophagy–lysosome target genes, which can be reversed by BRAFi. In conjunction with TFEB activation, BRAFi increases JNK2/p38-mediated phosphorylation/
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