Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer
Ji Won Kim,
Cuyler Luck,
Wei Wu,
Rovingaile Kriska Ponce,
Yone Kawe Lin,
Nehal Gupta,
Ross A. Okimoto
Affiliations
Ji Won Kim
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju, Republic of Korea
Cuyler Luck
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Wei Wu
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Rovingaile Kriska Ponce
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Yone Kawe Lin
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Nehal Gupta
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Ross A. Okimoto
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Summary: Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.
