PMID- 35145081 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20221022 IS - 2041-4889 (Electronic) VI - 13 IP - 2 DP - 2022 Feb 10 TI - Acquired temozolomide resistance in MGMT(low) gliomas is associated with regulation of homologous recombination repair by ROCK2. PG - 138 LID - 10.1038/s41419-022-04590-6 [doi] LID - 138 AB - It was reported that MGMT(low) gliomas may still be resistant to TMZ, while the mechanisms remain poorly understood. In this study, we demonstrated that rho-associated kinase 2 (ROCK2), a cytoskeleton regulator, was highly expressed in MGMT(low) recurrent gliomas, and its expression strongly correlated with poor overall survival (OS) time in a subset of MGMT(low) recurrent gliomas patients with TMZ therapy. And we also found that overactive ROCK2 enhanced homologous recombination repair (HR) in TMZ-resistant (TMZ-R) glioma cell lines with low MGMT expression. Silencing ROCK2 impaired HR repair, and induced double-strand break (DSB) and eradicated TMZ-R glioma cells in culture. Notably, in MGMT(low) TMZ-R models, as a key factor of HR, ataxia telangiectasia-mutated (ATM) expression was upregulated directly by hyper-activation of ROCK2 to improve HR efficiency. ROCK2 enhanced the binding of transcription factor zinc finger E-box binding homeobox 1 (ZEB1) to ATM promoter for increasing ATM expression. Moreover, ROCK2 transformed ZEB1 into a gene activator via Yes-associated protein 1 (YAP1). These results provide evidence for the use of ROCK inhibitors in the clinical therapy for MGMT(low) TMZ-resistant glioma. Our study also offered novel insights for improving therapeutic management of MGMT(low) gliomas. CI - (c) 2022. The Author(s). FAU - Zhang, Xin AU - Zhang X AUID- ORCID: 0000-0003-2452-360X AD - State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Li, Tao AU - Li T AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Yang, Mengdi AU - Yang M AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Du, Qianming AU - Du Q AUID- ORCID: 0000-0002-1092-2899 AD - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. AD - General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China. FAU - Wang, Rui AU - Wang R AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Fu, Bin AU - Fu B AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Tan, Yingying AU - Tan Y AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Cao, Mengran AU - Cao M AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Chen, Yaxin AU - Chen Y AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Wang, Qing AU - Wang Q AUID- ORCID: 0000-0001-8729-7211 AD - Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi, Jiangsu, China. wxwqnj@hotmail.com. FAU - Hu, Rong AU - Hu R AUID- ORCID: 0000-0003-2998-064X AD - State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. ronghu@cpu.edu.cn. LA - eng GR - BK20191140/Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)/ GR - 81672816/National Natural Science Foundation of China (National Science Foundation of China)/ GR - 81872337/National Natural Science Foundation of China/ GR - 82073185/National Natural Science Foundation of China/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220210 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.1.1.- (DNA Modification Methylases) RN - EC 2.1.1.63 (MGMT protein, human) RN - EC 2.7.11.1 (ROCK2 protein, human) RN - EC 2.7.11.1 (rho-Associated Kinases) RN - EC 6.5.1.- (DNA Repair Enzymes) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Antineoplastic Agents, Alkylating/pharmacology MH - *Brain Neoplasms/drug therapy/genetics MH - Cell Line, Tumor MH - DNA Modification Methylases/genetics/metabolism MH - DNA Repair Enzymes/genetics/metabolism MH - Drug Resistance, Neoplasm/genetics MH - *Glioma/drug therapy/genetics/metabolism MH - Humans MH - Neoplasm Recurrence, Local/drug therapy MH - Recombinational DNA Repair MH - Temozolomide/pharmacology MH - Tumor Suppressor Proteins/metabolism MH - *rho-Associated Kinases/genetics/metabolism PMC - PMC8831658 COIS- The authors declare no competing interests. EDAT- 2022/02/12 06:00 MHDA- 2022/04/09 06:00 PMCR- 2022/02/10 CRDT- 2022/02/11 05:34 PHST- 2021/06/29 00:00 [received] PHST- 2022/01/27 00:00 [accepted] PHST- 2022/01/05 00:00 [revised] PHST- 2022/02/11 05:34 [entrez] PHST- 2022/02/12 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] PHST- 2022/02/10 00:00 [pmc-release] AID - 10.1038/s41419-022-04590-6 [pii] AID - 4590 [pii] AID - 10.1038/s41419-022-04590-6 [doi] PST - epublish SO - Cell Death Dis. 2022 Feb 10;13(2):138. doi: 10.1038/s41419-022-04590-6.