Abstract 1904: Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis

Abstract

Abstract Hepatocyte nuclear factor 4 alpha (HNF4α) is one of the most ancient nuclear receptors known as a master regulator of hepatocytes in lipids, carbohydrates, and drug metabolism. It also works as a tumor suppressor to regulate cell cycle in hepatocellular carcinoma (HCC), but the ligand activating HNF4α has not yet been discovered thus far. Here we evaluated the effect of polyprenoic acid (PA), formerly known as an acyclic retinoid, on HNF4α activation in dysplastic nodule and HCC in vitro and in vivo. PDGF-C transgenic (Tg) mice was evaluated by Gd-EOB-DTPA-enhanced MRI to examine the effect of PA on HCC development in vivo. Whole exome sequence analysis was performed using Illumina Hiseq 2000 system. Contrast enhanced CT scan data of patients enrolled in previous phase II/III randomized placebo-controlled study were collected and analyzed (n = 124 for PA and 127 for placebo). PA treatment regressed the liver dysplastic nodule and a subset of HCCs in PDGF-C Tg mice evaluated by MRI. This tumor regression was accompanied with the reduction of accumulated gene mutations, inactivation of cell cycle, and transcriptional activation of HNF4α-target genes. The binding of PA on ligand binding domain of HNF4α was shown by docking simulation in silico and immunoprecipitation-mass spectrometry analysis in vitro. Transcriptional activation of HNF4α by PA was also verified using a luciferase reporter assay and binding of HNF4α on DNA binding elements. PA treatment in HCC cells immediately resulted in the degradation of HNF4α by ubiquitin-proteasome system with activation of DNA damage responses when cultured in lipid depleted medium. In vivo knockdown of HNF4A cancelled the effect of PA on regression of liver tumor growth in PDGF-C Tg mice. PA treatment (600 mg/day) suppressed the HCC development from dysplastic nodule compared with placebo in human with statistical significance (HR 0.41; 95% CI, 0.17~0.98, P = 0.046). Taken together, our data indicated that PA is the first-discovered HNF4α ligand to activate its function. PA activates the DNA damage responses and suppresses the accumulation of gene mutations especially in dysplastic nodule, warranting the future prospective study to evaluate the effect of PA on suppression of HCC development from dysplastic nodules in human. Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis [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 1904.