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.

SIN3阻遏物复合物和NAD依赖性脱乙酰基酶SIRT3控制细胞的生长，发育以及恶性转化。即便如此，对于这两种染色质修饰剂之间的串扰或它们之间的相互作用是否在治疗上也有所了解。在这里，我们描述了鉴定C _21-甾族化合物衍生物3- O-氯乙酰基-加加明A671的方法，该化合物在体外和临床前模型中均有效抑制小鼠和人T细胞淋巴瘤和红白血病的生长。A671通过与组蛋白去乙酰化酶复合物亚基SAP18（SIN3抑制物复合物的一个组成部分）直接相互作用而发挥抗肿瘤作用。这种相互作用稳定并激活了SAP18，从而导致SIRT3的转录抑制因此抑制增殖和细胞死亡。癌细胞对A671的抗性与SAP18激活减少和SIRT3持续表达相关。这些结果揭示了SAP18-SIN3-SIRT3轴，该轴可以被C _21类固醇药物药理靶向以抑制T细胞淋巴瘤和其他恶性肿瘤。