DNA methylation modifier LSH inhibits p53 ubiquitination and transactivates p53 to promote lipid metabolism.

Autor: Chen L; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China.; Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, China.; Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, China., Shi Y; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Liu N; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Wang Z; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Yang R; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Yan B; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China.; Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China., Liu X; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Lai W; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Liu Y; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Xiao D; Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China., Zhou H; Shanghai Institute of Material Medica, Chinese Academy of Sciences (CAS), 555 Zu Chongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China., Cheng Y; Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, Hunan, China., Cao Y; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China., Liu S; Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China., Xia Z; Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, China. xiazanxian@sklmg.edu.cn.; Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China. xiazanxian@sklmg.edu.cn., Tao Y; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China. taoyong@csu.edu.cn.; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. taoyong@csu.edu.cn.; Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, China. taoyong@csu.edu.cn.; Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China. taoyong@csu.edu.cn.; Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China. taoyong@csu.edu.cn.
Jazyk: angličtina
Zdroj: Epigenetics & chromatin [Epigenetics Chromatin] 2019 Oct 08; Vol. 12 (1), pp. 59. Date of Electronic Publication: 2019 Oct 08.
DOI: 10.1186/s13072-019-0302-9
Abstrakt: Background: The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown.
Results: Here, we present data suggesting that LSH regulates p53 in cis through two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH-PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivation in cis in lipid metabolism, especially lipid catabolism.
Conclusion: These findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer.
Databáze: MEDLINE
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