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.
Commun Biol. 2020 Dec 3;3(1):732. doi: 10.1038/s42003-020-01458-3.
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-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-steroidal agent to suppress T-cell lymphoma and other malignancies.
SIN3 抑制复合物和依赖 NAD 的去乙酰化酶 SIRT3 控制细胞生长、发育以及恶性转化。即便如此，人们对这两种染色质修饰物之间的相互作用知之甚少，或者是否对其进行了治疗探索。在这里，我们描述了一种 C-甾体衍生化合物 3-O-氯乙酰基-甘氨酸甲酯（A671）的鉴定，它能够在体外和临床前模型中强烈抑制小鼠和人 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 抑制复合物的一个组成部分）的直接相互作用发挥其抗肿瘤作用。这种相互作用稳定并激活 SAP18，导致 SIRT3 的转录抑制，从而抑制增殖和细胞死亡。癌细胞对 A671 的耐药性与 SAP18 激活的减少和 SIRT3 表达的持续相关。这些结果揭示了 SAP18-SIN3-SIRT3 轴，该轴可通过 C-甾体药物靶向抑制 T 细胞淋巴瘤和其他恶性肿瘤。
