NeuroD1 drives a KAT2A-FDFT1 signaling axis to promote cholesterol biosynthesis and hepatocellular carcinoma progression via histone H3K27 acetylation.

Abnormal lipid metabolism is one of the hallmarks of cancer. Lipid metabolic reprogramming, which has been observed in various tumors, could participate in tumor occurrence, invasion, and metastasis of tumors by regulating various carcinogenic signaling pathways. However, the molecular mechanism that regulates tumor cell lipid metabolic reprogramming has not been fully elucidated. Recent studies revealed that neurogenic differentiation factor 1 (NeuroD1) is upregulated in a variety of tumor cells, and is associated with tumorigenesis and poor prognosis. However, its role in tumor cell lipid metabolism remains unclear. Here, we found that NeuroD1 is highly expressed in hepatocellular carcinoma (HCC) cells and is associated with tumor cell cholesterol biosynthesis. We found that NeuroD1 enhances HCC cell cholesterol biosynthesis, leading to an increase in their viability. Mechanistically, NeuroD1 binds to the promoter of farnesyl diphosphate farnesyl transferase 1 (FDFT1), thereby activating its transcription activity. Furthermore, NeuroD1 can promote FDFT1 transcription through lysine acetyltransferase 2A-mediated H3K27 acetylation. Subsequently, we found that NeuroD1/FDFT1-mediated cholesterol biosynthesis is critical to the tumorigenic potential of HCC cells. These findings not only identify NeuroD1 as a regulator of lipid metabolism in tumor cells, but also reveal a novel molecular mechanism underlying its carcinogenic function.