Paradoxical oncogenic effects of hepatic Brca1 through modulating Bhmt

Abstract The well-established tumor suppressor, Breast Cancer Susceptibility Gene 1 (BRCA1), has been implicated in lipid metabolism and in paradoxically promoting hepatocellular carcinoma (HCC); yet its mechanistic role remains unknown. Here we show murine hepatic Brca1 loss protected against fatty liver, glucose intolerance and tumor development. Using single nuclear RNA sequencing, we found betaine-homocysteine S-methyltransferase (Bhmt) was suppressed with Brca1-deficiency. Concomitant knockdown of BRCA1 and BHMT in human hepatoma cells revealed additive accumulation of DNA double strand breaks and increased susceptibility to cell death. In our mouse model and human hepatoma cells, BHMT repression with BRCA1-deficiency was associated with downregulation of choline metabolism, an emerging hallmark of cancer. Metabolomics in hepatic Brca1-deficient mice further revealed related disruptions in choline metabolism. Together, our data show hepatic Brca1-deficiency protected against tumor formation by inducing cell death through exacerbating DNA damage and suppressing choline metabolism by inhibiting Bhmt expression, challenging the role of BRCA1 solely as a tumor suppressor.