Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells
Yicun Wang, Jinhui Wu, Hui Chen, Yang Yang, Chengwu Xiao, Xiaoming Yi, Changjie Shi, Ke Zhong, Haowei He, Yaoming Li, Zhenjie Wu, Guangxin Zhou, Qiu Rao, Xiaoxia Wang, Xiaodie Zhou, Gwen Lomberk, Bing Liu, Jianning Zhao, Jingping Ge, Wenquan Zhou, Xiaoyuan Chu, Cheng Chen, Xuhui Zhou, Linhui Wang, Kun‐Liang Guan, Le Qu
Abstract
Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.