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 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.

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Li, Shun, Song, Ying, Quach, Christine, Guo, Hongrui, Jang, Gyu-Beom, Maazi, Hadi, Zhao, Shihui, Sands, Nathaniel A.., Liu, Qingsong, In, Gino K.., Peng, David, Yuan, Weiming, Machida, Keigo, Yu, Min, Akbari, Omid, Hagiya, Ashley, Yang, Yongfei, Punj, Vasu, Tang, Liling, and Liang, Chengyu. Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance. 22296. 2019 Nature Communications (10):1.

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

Semantics

Type Source Name
drug DRUGBANK Aspartame
gene UNIPROT SDS
gene UNIPROT SBDS
drug DRUGBANK Sodium lauryl sulfate
gene UNIPROT NAGLU
gene UNIPROT SCN7A
gene UNIPROT NBAS
drug DRUGBANK Human Serum Albumin
gene UNIPROT RRAD
gene UNIPROT IDE
gene UNIPROT WASHC1
gene UNIPROT ZNF185
gene UNIPROT MIXL1
drug DRUGBANK Edetic Acid
drug DRUGBANK Tromethamine
gene UNIPROT CES2
gene UNIPROT CASP1
drug DRUGBANK Copper
gene UNIPROT TNMD
gene UNIPROT CYLD
drug DRUGBANK Tretamine
drug DRUGBANK Sodium acetate
gene UNIPROT HSD17B12
gene UNIPROT KIT
drug DRUGBANK Water
gene UNIPROT ADHFE1
drug DRUGBANK Hydrogen peroxide
drug DRUGBANK Ethanol
drug DRUGBANK Formaldehyde
gene UNIPROT SLC5A5
gene UNIPROT AOPEP
gene UNIPROT TSPO
gene UNIPROT CHRM3
gene UNIPROT BRD1
gene UNIPROT MBOAT4
gene UNIPROT JTB
gene UNIPROT NR1I2
gene UNIPROT NKX6-2
gene UNIPROT PARP1
gene UNIPROT COL11A2
gene UNIPROT ATP6V1H
gene UNIPROT NUBP1
gene UNIPROT RPS6KA1
gene UNIPROT RPS6KA2
gene UNIPROT RPS6KA3
gene UNIPROT CTBS
gene UNIPROT PCYT1B
gene UNIPROT PNMA3
gene UNIPROT PRDM6
gene UNIPROT EMD
gene UNIPROT SMCP
gene UNIPROT MOCOS
disease DOID MCS
drug DRUGBANK Calcium Phosphate
drug DRUGBANK L-Glutamine
gene UNIPROT C2
gene UNIPROT TNFSF14
gene UNIPROT MAL
gene UNIPROT MRTFA
gene UNIPROT TIRAP
gene UNIPROT MAGEE1
disease DOID neoplasm
gene UNIPROT ASIC5
disease DOID pancreatic tumor
gene UNIPROT CTRL
gene UNIPROT H2AFX
gene UNIPROT SNAI2
gene UNIPROT CTSD
drug DRUGBANK Rasagiline
gene UNIPROT FAM155B
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
gene UNIPROT VIM
gene UNIPROT SMAD3
gene UNIPROT SGSM3
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
gene UNIPROT ARHGAP9
gene UNIPROT NES
gene UNIPROT TFEB
pathway BSID Lysosome
pathway BSID Melanoma
disease DOID melanoma
gene UNIPROT BRAF
disease MESH melanoma
gene UNIPROT COL9A3
drug DRUGBANK Coenzyme M
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT COL9A2
disease DOID Cancer
gene UNIPROT SCN8A
gene UNIPROT SLC22A3
gene UNIPROT ITK
disease MESH tumor
gene UNIPROT CRK
gene UNIPROT GRAP2
gene UNIPROT AHSA1
gene UNIPROT POLDIP2
gene UNIPROT MAPK14
gene UNIPROT AIMP2
gene UNIPROT MAPK9
gene UNIPROT ZKSCAN3
gene UNIPROT EPHB2
gene UNIPROT MAPK1
disease MESH senescence
disease MESH tumorigenesis
disease DOID noma
disease MESH noma
disease MESH growth
gene UNIPROT CAD
gene UNIPROT DFFB
gene UNIPROT ACOD1
gene UNIPROT CD40LG
gene UNIPROT TRAF2
gene UNIPROT ACP5
gene UNIPROT SCYL1
gene UNIPROT TDRD7
gene UNIPROT FAM110A
gene UNIPROT F10
pathway BSID Apoptosis
gene UNIPROT FURIN
disease DOID SCID
gene UNIPROT ATN1
gene UNIPROT EPHB1
gene UNIPROT ELK3
gene UNIPROT SLC6A2
gene UNIPROT PRRT2
gene UNIPROT OCA2
gene UNIPROT B3GALNT1
disease MESH **P
drug DRUGBANK Proline
gene UNIPROT CTBP1
drug DRUGBANK Methyl isocyanate
disease MESH dissociation
gene UNIPROT IK
gene UNIPROT DYRK3
drug DRUGBANK Dimethyl sulfoxide
gene UNIPROT PCID2
disease MESH metastasis
gene UNIPROT GSTK1
gene UNIPROT SLCO6A1
gene UNIPROT ATG5
gene UNIPROT BECN1
drug DRUGBANK Chloroquine
gene UNIPROT SLC35G1
gene UNIPROT SNAI1
gene UNIPROT SMAD2
gene UNIPROT ZEB1
gene UNIPROT TWIST1
gene UNIPROT TNF
disease MESH dif
gene UNIPROT THOP1
gene UNIPROT DLX4
gene UNIPROT GEN1
gene UNIPROT SSRP1
gene UNIPROT ELANE
disease MESH genomic instability
gene UNIPROT ROS1
drug DRUGBANK Rosoxacin
gene UNIPROT RAB8A
gene UNIPROT EIF2AK3
gene UNIPROT EIF2AK2
gene UNIPROT HSPA5
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
gene UNIPROT MITF
disease MESH multiple
gene UNIPROT LAMP1
gene UNIPROT HERPUD1
gene UNIPROT SNAP25
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT KHDRBS1
gene UNIPROT GTF2H1
gene UNIPROT DCTN4
gene UNIPROT SQSTM1
gene UNIPROT NUP62
gene UNIPROT MAP1LC3A
gene UNIPROT REG1A
gene UNIPROT ZHX1-C8orf768q24.13
gene UNIPROT JUN
drug DRUGBANK Zinc
disease MESH Starvation
drug DRUGBANK Sirolimus
gene UNIPROT TFE3
disease DOID microphthalmia
disease MESH microphthalmia
gene UNIPROT XPO1
gene UNIPROT MCOLN1
gene UNIPROT MAPK8
gene UNIPROT IPO8
gene UNIPROT AKT1
gene UNIPROT EFNA5
gene UNIPROT RRAGB
gene UNIPROT DEPDC5
gene UNIPROT MTOR
gene UNIPROT LSM4
gene UNIPROT UCMA
gene UNIPROT LGALSL
gene UNIPROT GRP
drug DRUGBANK L-Asparagine
gene UNIPROT NRAS

Original Article

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