ELP3 是 Elongator 复合物的催化亚基，是一种乙酰转移酶，与肿瘤进展相关。然而，ELP3致癌功能的细节仍不清楚。在这里，我们发现 ELP3 稳定 c-Myc，以不依赖乙酰转移酶的方式促进肿瘤发生。从机械角度来看，ELP3 与 E3 连接酶 FBXW7β 竞争 c-Myc 结合，从而抑制 FBXW7β 介导的 c-Myc 泛素化和蛋白酶体降解。 ELP3 敲低可减少糖酵解和谷氨酰胺分解，并通过下调 c-Myc 显着延缓细胞增殖和异种移植物生长，而这种效应可通过重建 c-Myc 表达来挽救。此外，ELP3和c-Myc在结直肠癌和肝细胞癌中过度表达，且呈正相关。总之，我们阐明了 ELP3 通过稳定 c-Myc 促进肿瘤发生的新功能，表明抑制 ELP3 是治疗 c-Myc 驱动的癌症的潜在策略。© 作者 2023。牛津大学出版大学出版社代表中国科学院上海生命科学研究院生物化学与细胞生物学研究所。

ELP3, the catalytic subunit of Elongator complex, is an acetyltransferase and associated with tumor progression. However, the detail of ELP3 oncogenic function remains largely unclear. Here, we found that ELP3 stabilizes c-Myc to promote tumorigenesis in an acetyltransferase-independent manner. Mechanically, ELP3 competes with the E3-ligase FBXW7β for c-Myc binding, resulting in the inhibition of FBXW7β-mediated ubiquitination and proteasomal degradation of c-Myc. ELP3-knockdown diminishes glycolysis and glutaminolysis and dramatically retards cell proliferation and xenograft growth by downregulating c-Myc, and such effects are rescued by reconstitution of c-Myc expression. Moreover, ELP3 and c-Myc were overexpressed with a positive correlation in colorectal cancer and hepatocellular carcinoma. Taken together, we elucidate a new function of ELP3 in promoting tumorigenesis by stabilizing c-Myc, suggesting that inhibition of ELP3 is a potential strategy for the therapy of c-Myc-driven carcinomas.© The Author(s) 2023. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.