Pbrm1欠損は、胆管細胞分化と胆管癌形成を促進する許容的なクロマチン状態を誘導する

The SWI/SNF ATP-dependent chromatin remodeling complex regulates transcriptional machinery access and is critical in normal physiology and cancer development. PBRM1, a key subunit of this complex, is frequently mutated in intrahepatic cholangiocarcinoma (iCCA). This study aims to explore the role of PBRM1 in liver physiology and its involvement in iCCA development.

Liver-specific Pbrm1 knockout (Pbrm1 KO) mice were generated to assess the effects of Pbrm1 loss under various conditions. These mice were exposed to a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet to induce cholestatic injury and were also subjected to a high-fat diet to evaluate susceptibility to liver steatosis. Chromatin accessibility and gene expression under both normal and injury conditions were examined. Additionally, the impact of Pbrm1 loss was analyzed in combination with an activating Kras^G12D mutation to study cancer development.

Pbrm1 KO mice exhibited increased susceptibility to cholestatic injury, with an enhanced ductular reaction. Loss of Pbrm1 reduced chromatin accessibility at hepatocyte-specific and metabolically important genes, though RNA expression remained unaffected during homeostasis. Following cholestatic injury, hepatocyte-specific gene expression was significantly reduced compared to wild-type controls. Pbrm1 KO mice also showed heightened vulnerability to high-fat diet-induced liver steatosis. When combined with Kras^G12D mutation, Pbrm1 KO/Kras^G12D mice had shorter survival and were more likely to develop cholangiocarcinomas, whereas Pbrm1 wild type/Kras^G12D mice predominantly developed hepatocellular neoplasms. PBRM1-deficient organoids were highly sensitive to the EZH2 inhibitor tazemetostat, while effects on allografts were limited.

PBRM1 maintains chromatin accessibility for hepatocyte differentiation-related genes. Its loss promotes differentiation toward cholangiocytes during injury or tumorigenesis, driving iCCA development.