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.
See also: F Zanconato & S Piccolo (March 2016)
BRAF V600E mutant melanoma cells undergo active actin cytoskeletal remodeling in response to the BRAF inhibitor PLX4032, and the remodeling promotes nuclear localization of YAP/TAZ oncoproteins, conferring adaptive resistance to PLX4032.
The development of PLX4032 resistance in melanoma cell lines is accompanied by increases in both actin stress fiber formation and cell spreading on substrates.
PLX4032‐resistant melanoma cells exhibit higher levels of YAP/TAZ nuclear localization and transcriptional activity.
Inhibition of actin filament assembly or actin cytoskeletal tension suppresses YAP/TAZ activation and PLX4032 resistance in melanoma cells.
Depletion of YAP/TAZ restores PLX4032 sensitivity in resistant cells, whereas overexpression of constitutively active YAP induces PLX4032 resistance in non‐resistant melanoma cells.
The EMBO Journal (2016) 35: 462–478
- Received May 18, 2015.
- Revision received September 6, 2015.
- Accepted September 11, 2015.
- © 2015 The Authors
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