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

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 i...

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Bibliographic Details
Published in:Communications biology 2020-12, Vol.3 (1), p.732-732, Article 732
Main Authors: Gajendran, Babu, Varier, Krishnapriya M., Liu, Wuling, Wang, Chunlin, Sample, Klarke M., Zacksenhaus, Eldad, Juiwei, Cui, Huang, LieJun, Hao, XiaoJiang, Ben-David, Yaacov
Format: Article
Language:English
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Biology
Biomedical and Life Sciences
Cell death
Cell growth
Cell proliferation
Chromatin
Erythroleukemia
Histone deacetylase
Life Sciences
Lymphocytes T
Lymphoma
NAD
T-cell lymphoma
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Summary: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. Gajendran et al. show that a C21-steroidal derivative called A671, 3-O-chloroacetyl-gagamine, suppresses the growth of T-cell lymphoma in mice. They find that A671 activates SAP18 to suppress the transcription of SIRT3, inhibiting cell growth. This study presents a new pharmacological target pathway for T-cell lymphoma.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-020-01458-3