恶性肿瘤中突变率最高的基因是p53,发现靶向突变型p53肿瘤的分子调控机制是肿瘤研究的难点。我们前期研究揭示了调控p53蛋白稳定性的新机制（PNAS 2017）及p53下游靶基因Slc7a11参与调控细胞铁死亡新机理（Hepatology 2017，PNAS 2019），成果受到国际同行高度关注。通过小分子库的系统性筛选，结合大量体内、外功能实验，我们发现SIRT1可以特异调控突变型p53。本项目拟利用生物学前沿技术，运用条件性Sirt1及突变型p53基因敲除及转基因小鼠模型，深入研究SIRT1调控突变型p53基因的协同致死效应及其分子机制，为突变型p53恶性肿瘤的分子靶点筛选提供重要科学依据。

Mutations in the p53 tumor suppressor gene are the most frequent genetic alterations throughout the entire spectrum of cancer. In clinic, p53 mutated cancer has been associated with poor prognosis. However, it remains challenge to specifically targeting mutated p53. The applicant has been working on functionally screening and identifying novel cancer targets for decades and established a strong research team and functional screening platforms. Recently, the applicant and her research team uncovered the novel molecular mechanism of p53 protein stabilization (PNAS, 2017 Co-corresponding author) and the novel function of p53 targeted gene (Slc7a11) in the process of ferroptosis (PNAS 2019, Hepatology 2017, Co-corresponding author). Additional studies have mechanistically elucidated molecular mechanisms of tumor suppressor DAB2IP (Nature Medicine 2010, First author). The aim of this proposal is to identify potential epigenetic regulators for targeting p53 mutated cancer through synthetic lethal screens. Through chemical genomics screening, we identified a class of activators of SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, showed preferential growth inhibitory effect on mutant p53 cell lines. In contrast, inhibition of SIRT1 completely rescues SIRT1-mediated lethal phenotypes. Therefore, we hypothesized that the synthetic lethal relationship between mutant p53 and activation of SIRT1 might be a novel therapeutic strategy in treating a wide spectrum of mutant p53-harboring cancers. To test this hypothesis, we propose to systemically and mechanistically study the synthetic lethal relationship between SIRT1 activation and p53 mutations in a panel of cancer cell lines and in p53 mutated murine cancer models using integrated genomic and proteomic profiling approach followed by functional validation. We believe the findings of this proposal, if approved, could not only extend our current understanding of the epigenetic regulation of p53 mutation in tumorigenesis, but also to elucidate molecular mechanisms of the synthetic lethality between SIRT1 and mutated p53. Importantly, this proposal provides experimental evidence for further developing potential novel cancer therapeutics for targeting mutated p53.