A C21-steroidal derivative suppresses T-cell lymphoma in mice by inhibiting SIRT3 via SAP18-SIN3.

Autor: Gajendran B; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China., Varier KM; Department of Medical Biochemistry, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600113, India., Liu W; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China., Wang C; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China., Sample KM; The National Health Commission's Key Laboratory of Immunological Pulmonary Disease, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou University, Guiyang, Guizhou, 550002, China., Zacksenhaus E; Department of Medicine, University of Toronto, Toronto, M5G 2M1, ON, Canada.; Division of Advanced Diagnostics, Toronto General Research Institute-University Health Network, Toronto, ON, Canada., Juiwei C; The Cancer Center of the First Hospital of Jilin University, Changchun, Jilin, 130021, China., Huang L; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China. huangliejun@126.com.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China. huangliejun@126.com., Hao X; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China. haoxj@mail.kib.ac.cn.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China. haoxj@mail.kib.ac.cn., Ben-David Y; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China. yaacovbendavid@hotmail.com.; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, China. yaacovbendavid@hotmail.com.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2020 Dec 03; Vol. 3 (1), pp. 732. Date of Electronic Publication: 2020 Dec 03.
DOI: 10.1038/s42003-020-01458-3
Abstrakt: The SIN3 repressor complex and the NAD-dependent deacetylase SIRT3 control cell growth, and development as well as malignant transformation. Even then, a little known about cross-talks between these two chromatin modifiers or whether their interaction explored therapeutically. Here we describe the identification of a C 21 -steroidal derivative compound, 3-O-chloroacetyl-gagamine, A671, which potently suppresses the growth of mouse and human T-cell lymphoma and erythroleukemia in vitro and preclinical models. A671 exerts its anti-neoplastic effects by direct interaction with Histone deacetylase complex subunit SAP18, a component of the SIN3 suppressor complex. This interaction stabilizes and activates SAP18, leading to transcriptional suppression of SIRT3, consequently to inhibition of proliferation and cell death. The resistance of cancer cells to A671 correlated with diminished SAP18 activation and sustained SIRT3 expression. These results uncover the SAP18-SIN3-SIRT3 axis that can be pharmacologically targeted by a C 21 -steroidal agent to suppress T-cell lymphoma and other malignancies.
Databáze: MEDLINE
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