The upregulation of GDF15 is controlled epigenetically by oncogenic TCF19 signaling in human hepatocellular carcinoma

Growth differentiation factor 15 (GDF15) plays an important role in the progression of hepatocellular carcinoma (HCC) and chronic liver disease, but its regulatory mechanisms are still unclear. Here, we found that the histone methylation reader protein transcription factor 19 (TCF19) was significantly positively correlated with and regulated GDF15 expression. RNA sequencing and chromatin immunoprecipitation (ChIP) revealed that TCF19 regulated GDF15 expression by directly binding to its promoter through the plant homeodomain (PHD) finger, recognizing H3K4me3. Coculture analysis suggests that TCF19 promoted the proliferation of HCC cells and the activation of hepatic stellate cell line LX2 by increasing the extracellular expression level of GDF15. We also found that Ras-related nuclear protein (RAN) might mediate the nuclear localization of TCF19, thereby affecting GDF15 expression and its pro-proliferative function. In summary, we demonstrated that GDF15 is positively regulated by TCF19, promoting the development of HCC.