Abstract
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 C21-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 C21-steroidal agent to suppress T-cell lymphoma and other malignancies.
Highlights
The SIN3 repressor complex and the NAD-dependent deacetylase SIRT3 control cell growth, and development as well as malignant transformation
We show that A671 acts as an HDAC-class III inhibitor that suppresses transcription of SIRT3, leading to apoptosis in culture and inhibition of leukemia and lymphoma in vivo
We show that A671 directly interacts with SIN3 Associated Protein 18 (SAP18), inducing activation of the SAP18/SIN3 complex, and transcriptional silencing of SIRT3
Summary
The SIN3 repressor complex and the NAD-dependent deacetylase SIRT3 control cell growth, and development as well as malignant transformation. A671 exerts its antineoplastic 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, 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 C21-steroidal agent to suppress T-cell lymphoma and other malignancies. We show that A671 directly interacts with SAP18, inducing activation of the SAP18/SIN3 complex, and transcriptional silencing of SIRT3 These results uncover unknown regulation of SIRT3 by the SIN3 complex via SAP18, and identify A671 as a potent inhibitor for the treatment of erythroleukemia, T-cell lymphoma, and possibly other malignancies
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