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Hepatocyte nuclear factor 3γ (HNF3γ) is a hepatocyte nuclear factor, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unclear. Herein, we report that HNF3γ expression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival. Moreover, our data suggested that the HNF3γ reduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γ mRNA. HNF3γ expression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells. Interestingly, HNF3γ delivery promoted differentiation of not only HCC cells but also liver CSCs, which led to suppression of HCC growth. Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules, which could synergistically facilitate HCC cell differentiation. More importantly, enforced HNF3γ expression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression, which are major membrane transporters for sorafenib uptake. Clinical investigation showed that patient-derived HCC xenografts with high HNF3γ expression exhibited a sorafenib response and patients with high HCC HNF3γ levels benefited from sorafenib therapy. Together, these results suggest that HNF3γ plays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.

m6A RNA methylation-mediated HNF3γ reduction renders hepatocellular carcinoma dedifferentiation and sorafenib resistance