Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells
| Autor: | Linhui Wang, Jinhui Wu, Ke Zhong, Yang Yang, Gwen Lomberk, Wen-Quan Zhou, Xiaoyuan Chu, Xiaoming Yi, Jianning Zhao, Changjie Shi, Bing Liu, Hui Chen, Kun-Liang Guan, Haowei He, Xiaoxia Wang, Yaoming Li, Jing-Ping Ge, Guangxin Zhou, Le Qu, Xuhui Zhou, Cheng Chen, Qiu Rao, Zhenjie Wu, Chengwu Xiao, Xiaodie Zhou, Yicun Wang |
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| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Biology medicine.disease_cause law.invention 03 medical and health sciences 0302 clinical medicine Rare Diseases Transcription (biology) law Cancer stem cell medicine Genetics SIN3A CRISPR Humans 2.1 Biological and endogenous factors Epigenetics Research Articles 030304 developmental biology Cancer 0303 health sciences Multidisciplinary Human Genome SciAdv r-articles Sarcoma Cell Biology medicine.disease Stem Cell Research Repressor Proteins 030220 oncology & carcinogenesis Cancer research Neoplastic Stem Cells Suppressor Stem Cell Research - Nonembryonic - Non-Human CRISPR-Cas Systems Carcinogenesis Apoptosis Regulatory Proteins Research Article |
| Zdroj: | Science advances, vol 7, iss 5 Science Advances |
| Popis: | KLF11 is a negative regulator of CSC stemness in sarcoma by repressing YAP/TEAD-dependent transcription. 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. |
| Databáze: | OpenAIRE |
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