Aurora-A-mediated cytosolic localization of Maf1 promotes cell proliferation via regulating mitochondrial function in HCC.

Maf1 is a well-known RNA polymerase III repressor and functions as a tumor suppressor due to its role in inhibiting tRNA synthesis. However, the role of Maf1 in hepatocellular carcinoma (HCC) remains unclear. This study identified Aurora-A as a novel upstream regulator of Maf1 in HCC. We demonstrated that Aurora-A interacts with the C domain of Maf1 and phosphorylates it at Threonine-212, leading to increased protein stability and cytosolic accumulation of Maf1. Importantly, the Aurora-A-enhanced cytosolic localization of Maf1 promotes mitochondrial dysfunction and glycolytic activity, ultimately driving HCC cell proliferation. In contrast, mutation of the Thr-212 site abolishes these effects, confirming its critical role. Significantly, elevated Maf-1 expression correlates with unfavorable clinical outcomes in HCC, particularly among patients with high Aurora-A expression. Furthermore, HCC cells with overexpressed Maf1 have heightened sensitivity to Aurora-A inhibitors, suggesting a potential therapeutic vulnerability. Our study uncovers a non-canonical, oncogenic role of Maf1 in HCC and highlights the Aurora-A-Maf1 axis as a promising target for personalized cancer therapy.