SIRT1 is a NAD⁺‐dependent deacetylase that controls key metabolic and signaling pathways, including inactivating the p53 tumor suppressor. However, the mechanisms controlling SIRT1 enzymatic activity in the context of cancer are unclear. Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1. CSAG2 is normally restricted to expression in the male germline but is frequently re‐activated in cancers. CSAG2 is necessary for cancer cell proliferation and promotes tumorigenesis in vivo. Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. Mechanistically, CSAG2 binds SIRT1 catalytic domain and promotes activity independent of altering substrate affinity. Together, our results identify a previously undescribed mechanism for SIRT1 activation in cancer cells and highlight unanticipated approaches to therapeutically modulate SIRT1.

中文翻译：

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CSAG2 是 SIRT1 的癌症特异性激活剂。

SIRT1 是一种 NAD ⁺依赖性脱乙酰酶，可控制关键的代谢和信号通路，包括使 p53 肿瘤抑制因子失活。然而，在癌症背景下控制 SIRT1 酶活性的机制尚不清楚。在这里，我们表明以前未描述的 CSAG2 蛋白是 SIRT1 的直接激活剂。CSAG2 通常仅限于在雄性生殖系中表达，但经常在癌症中重新激活。CSAG2是癌细胞增殖所必需的并促进体内肿瘤发生. 生化研究表明，CSAG2 直接结合并刺激 SIRT1 对多种底物的活性。重要的是，CSAG2 增强 SIRT1 介导的 p53 去乙酰化，抑制 p53 转录活性，并提高细胞对基因毒性应激反应的存活率。从机制上讲，CSAG2 结合 SIRT1 催化结构域并促进与改变底物亲和力无关的活性。总之，我们的结果确定了以前未描述的癌细胞中 SIRT1 激活的机制，并强调了治疗调节 SIRT1 的意想不到的方法。