Ji Won Kim^1,2, Cuyler Luck¹, Wei Wu¹, Rovingaile Kriska Ponce¹, Yone Kawe Lin¹, Nehal Gupta¹, Ross A. Okimoto^1,3,4

¹Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
²Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju, Republic of Korea
³Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

Corresponding author: Ross A Okimoto

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.