Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Cell Rep. 2023 Mar 28;42(3):112230. doi: 10.1016/j.celrep.2023.112230. Epub 2023 Mar 9.
Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation of repressors such as MDM2 and MDM4, is a hallmark of cancer. Although many inhibitors of the p53-MDM2/4 interaction have been developed, such as Nutlin, their therapeutic value is limited by highly heterogeneous cellular responses. We report here a multi-omics investigation of the cellular response to MDM2/4 inhibitors, leading to identification of FAM193A as a widespread regulator of p53 function. CRISPR screening identified FAM193A as necessary for the response to Nutlin. FAM193A expression correlates with Nutlin sensitivity across hundreds of cell lines. Furthermore, genetic codependency data highlight FAM193A as a component of the p53 pathway across diverse tumor types. Mechanistically, FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the p53 transcriptional program. Last, FAM193A expression is associated with better prognosis in multiple malignancies. Altogether, these results identify FAM193A as a positive regulator of p53.
p53 肿瘤抑制因子的失活，无论是通过突变还是通过 MDM2 和 MDM4 等抑制剂的过度激活，都是癌症的一个标志。尽管已经开发出许多 p53-MDM2/4 相互作用的抑制剂，如 Nutlin，但它们的治疗价值受到高度异质的细胞反应的限制。我们在这里报告了对 MDM2/4 抑制剂的细胞反应的多组学研究，导致鉴定出 FAM193A 是 p53 功能的广泛调节剂。CRISPR 筛选确定 FAM193A 是对 Nutlin 反应所必需的。FAM193A 的表达与数百种细胞系对 Nutlin 的敏感性相关。此外，遗传相互依赖性数据突出了 FAM193A 作为不同肿瘤类型中 p53 途径的一个组成部分。在机制上，FAM193A 与 MDM4 相互作用，FAM193A 的耗竭稳定了 MDM4 并抑制了 p53 转录程序。最后，FAM193A 的表达与多种恶性肿瘤的预后较好相关。总之，这些结果表明 FAM193A 是 p53 的正调节剂。
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