SRS90 Patey Prize Entrant - JMJD2A epigenetically regulates hepatocellular carcinoma metabolism

Abstract Hepatocellular carcinoma (HCC) is an aggressive malignancy that marks the sixth most common cancer worldwide. Regardless of aetiology, progression of HCC is variable and influenced by non-genetic factors, pointing to its epigenetic nature. Our goal was to characterize epigenetic modifications involved in HCC development and evaluate their potential as therapeutic targets. We have established four liver cancer cell lines resistant to three chemotherapeutic drugs. Transcriptomic profiling revealed up-regulation of lysine demethylase JMJD2A in chemoresistant cells. Screening of 182 epigenetic compounds showed that JMJD2A inhibition suppresses liver cancer cell growth. Oncogenic properties of JMJD2A were verified through a series of functional assays following JMJD2A knockdown. Specifically, by employing colorimetric and luminescence-based assays, JMJD2A knockdown significantly suppressed liver cancer cell growth. Similarly, stem cell properties were also affected by JMJD2A knockdown, as assessed by spheroid formation assays and expression analyses of cancer stem cell markers. Importantly, RNA-Sequencing profiling and bioinformatic analyses revealed that metabolic pathways are predicted to be significantly dysregulated. We have further employed microRNA profiling and identified microRNA-137 (miR-137) as a possible regulator of JMJD2A expression. The regulatory role of miR-137 was verified by RT-qPCR and western blot. Finally, through immunohistochemical and RT-qPCR analyses, we show that JMJD2A expression is increased in liver cancer tissues and positively correlated with disease progression. Our final goal is to explore the therapeutic potential of JMJD2A, using inhibitors and/or microRNA mimics, by employing a novel liver cancer-on-a-chip technology.