ELP3, the catalytic subunit of the 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. Mechanistically, 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 the reconstitution of c-Myc expression. Moreover, ELP3 and c-Myc were found 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 treating c-Myc-driven carcinomas.
