title: Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation.
abstract: The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Min Hwan
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Jongshin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Hyowon
authors.initials: H
authors.lastname: Hong
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Si-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: June-Koo
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Jung
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea joonkim@kaist.ac.kr.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012313:RNA / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000077484:Vemurafenib; D000091102:YAP-Signaling Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077484:Vemurafenib; D012313:RNA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor resistance; TAZ; YAP; actin cytoskeleton; melanoma