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

Shun Li, Ying Song, Christine Quach, Hongrui Guo, Gyu-Beom Jang, Hadi Maazi, Shihui Zhao, Nathaniel A. Sands, Qingsong Liu, Gino K. In, David Peng, Weiming Yuan, Keigo Machida, Min Yu, Omid Akbari, Ashley Hagiya, Yongfei Yang, Vasu Punj, Liling Tang () and Chengyu Liang ()
Additional contact information
Shun Li: University of Southern California
Ying Song: University of Southern California
Christine Quach: University of Southern California
Hongrui Guo: University of Southern California
Gyu-Beom Jang: University of Southern California
Hadi Maazi: University of Southern California
Shihui Zhao: University of Southern California
Nathaniel A. Sands: University of Southern California
Qingsong Liu: Chinese Academy of Sciences
Gino K. In: University of Southern California
David Peng: University of Southern California
Weiming Yuan: University of Southern California
Keigo Machida: University of Southern California
Min Yu: University of Southern California
Omid Akbari: University of Southern California
Ashley Hagiya: University of Southern California
Yongfei Yang: University of Southern California
Vasu Punj: University of Southern California
Liling Tang: Chongqing University
Chengyu Liang: University of Southern California

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09634-8

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