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

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

Publication date: Apr 12, 2019

Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAF-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 BRAF 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.

Li, S., Song, Y., Quach, C., Guo, H., Jang, G.B., Maazi, H., Zhao, S., Sands, N.A., Liu, Q., In, G.K., Peng, D., Yuan, W., Machida, K., Yu, M., Akbari, O., Hagiya, A., Yang, Y., , Punj, Tang, L., and Liang, C. Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance. 22301. 2019 Nat Commun (10):1.

Concepts Keywords
Autophagy MTORC1
Biogenesis BRAF
BRAF Autophagy
BRAF Inhibitor Melanoma
Chemoresistance TFEB
Coupling Branches of biology
EMT BRAF melanoma
ERK Tumor
Homeostasis
Lysosomal
Lysosome
Melanoma
Metastatic
MTORC1
Mutant
Oncogenic
P38 MAPK
Phosphorylated
Phosphorylation
Repressor
Stress
Transcription Factor
Transdifferentiation
Translocation
Tumor
Xenografts

Semantics

Type Source Name
gene UNIPROT SLC22A3
gene UNIPROT ITK
disease MESH tumor
gene UNIPROT CRK
gene UNIPROT AHSA1
gene UNIPROT GRAP2
gene UNIPROT POLDIP2
gene UNIPROT MAPK14
gene UNIPROT AIMP2
gene UNIPROT MAPK9
gene UNIPROT ZKSCAN3
gene UNIPROT EPHB2
gene UNIPROT MAPK1
gene UNIPROT TFEB
pathway BSID Lysosome
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT BRAF

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