The Upregulation of Growth Differentiation Factor 15 is Controlled Epigenetically by Oncogenic RAN/TCF19 Signaling in Human Hepatocellular Carcinoma

Abstract

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) could 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 and providing important insights into the role of PHD finger proteins in HCC.

Note:
Funding Information: This work was supported by the Natural Science Foundation of Zhejiang Province [Grant Nos. LY22H160017]; the Start-up Grant of HZNU (4275C50222204072) (to Heng Dong).

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: HCC tissues were obtained from the Hospital Affiliated of Hangzhou Normal University, and the study was approved by its medical ethics committee (2020(E02)-KS-014). The research was conducted in accordance with the principles of the Declaration of Helsinki.

This experiment was approved by the Animal Ethical and Welfare Committee of Hangzhou Normal University (HSD-20231218-01).

Keywords: GDF15, TCF19, HCC, PHD, Ran