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Nat Commun. 2019 Apr 12;10(1):1693. doi: 10.1038/s41467-019-09634-8.

Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance.

Author information

1
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
2
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
3
College of Veterinary Medicine, Sichuan Agriculture University, Chengdu, 611130, China.
4
High Magnetic Field Laboratory, Chinese Academy of Sciences, 350 Shushan Hu Road, Hefei, 230031, China.
5
Norris Comprehensive Cancer, Division of Oncology, University of Southern California, Los Angeles, CA, 90033, USA.
6
Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
7
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
8
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
9
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
10
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China. tangliling@cqu.edu.cn.
11
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. chengyu.liang@med.usc.edu.

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.

PMID:
30979895
PMCID:
PMC6461621
DOI:
10.1038/s41467-019-09634-8
[Indexed for MEDLINE]
Free PMC Article

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