CSAG2 is a cancer-specific activator of SIRT1.

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.