LAUSR

The pro-proliferation transcription factor FoxM1 is over-expressed mainly in high-grade cancers. However, the significance of its over-expression in cancers, including poorly differentiated hepatocellular carcinoma (HCC), is not known. Here we provide evidence for a causal role of the over-expressed FoxM1 in driving high-grade progression of HCC. Immunohistochemical staining of human HCC specimens revealed opposite expression patterns of FoxM1 and the liver differentiation genes FoxA1/A2. Moreover, using a transgenic mouse model for oncogenic Ras-driven HCC as well as cell-based studies, we provide in vivo genetic evidence for a direct repression of FoxA1/A2 by FoxM1. Interestingly, FoxM1 represses these differentiation genes mainly in G1 phase, a phase in the cell cycle in which cells can undergo differentiation. Moreover, repression of FoxA1/A2 in G1 phase is important, as these genes are capable of inhibiting expression of the pluripotency genes that are mainly expressed in S/G2 phases. Also, we show that FoxA1/A2 inhibit expression of FoxM1 by inhibiting binding of FoxM1 to its own promoter and thus blocking its auto-activation. Our observations identify a significant new mechanism in which FoxM1 and the FoxA genes play opposing roles that determine the differentiation state of the HCC cells. Citation Format: Vaibhav Chand, Akshay Pandey, Dragana Kopanja, Grace Guzman, Pradip Raychaudhuri. Opposing roles of FoxM1 and the hepatic specification genes FoxA1/A2 dictate differentiation state of liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1504.