PRMT5 imposed a dual repression on DDIT3 transcription to promote the malignancy of hepatocellular carcinoma

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Dysregulation of the epigenetic modifier PRMT5 contributes to the proliferation and metastasis of cancers, and its inhibition has displayed promising therapeutic effect on malignant tumors. However, the pathogenic mechanism and therapeutic potential of targeting PRMT5 in HCC remain unclear.

AIM

To elucidate the molecular mechanisms by which PRMT5 promotes HCC progression and to provide a rationale for novel therapeutic strategies targeting PRMT5.

METHODS

The correlation between PRMT5 expression and patient prognosis was analyzed using an online database (GEPIA2). Subsequently, the functional impact of PRMT5 was evaluated in vitro through cell viability, clonogenic formation, and apoptosis assays in HCC cell lines. Mechanistically, chromatin immunoprecipitation, co-immunoprecipitation, and promoter activity assays were used to investigate the binding PRMT5 and histone modification (H4R3me2) on the DDIT3 promoter, and its interaction with STAT3. The anti-tumor efficacy of HLCL-61 was evaluated in subcutaneous xenograft mouse models using both cell line-derived xenografts and patient-derived xenografts.

RESULTS

Our study found that high PRMT5 expression was correlated with a worse prognosis of HCC, and inhibition of PRMT5 expression significantly decreased the viability of HCC cells by inducing apoptosis. In the mechanistic study, we discovered that PRMT5 could bind to the DDIT3 promoter and increase the H4R3me2 level on it to repress DDIT3 transcription. Meanwhile, PRMT5 interacted with the coiled-coil domain of STAT3 and recruited it to the DDIT3 promoter to conjointly inhibit promoter activity. In addition, we evaluated that the PRMT5 inhibitor HLCL-61 and found that it exhibited excellent inhibitory efficacy on HCC cells and tissue derived tumors.

CONCLUSION

PRMT5 served as an adaptor of STAT3, displaying a dual inhibitory role in DDIT3 transcription to promote apoptosis resistance, and its inhibitor HLCL-61 represents a potential alternative therapeutic approach to treat HCC.

Keywords: Hepatocellular carcinoma; PRMT5; HLCL-61; Apoptosis; Symmetrical dimethylation

Core Tip: High PRMT5 expression was correlated with a worse prognosis of hepatocellular carcinoma (HCC), and inhibition of PRMT5 expression significantly decreased the viability of HCC cells by inducing apoptosis. Mechanistically, PRMT5 dually suppressed the promoter activity of the apoptosis-inducing factor DDIT3 by increasing H4R3me2 modification and recruiting STAT3 to its promoter. The PRMT5 inhibitor HLCL-61 exerted excellent inhibitory efficacy on HCC cells and tissue derived tumors. In general, our study demonstrated that PRMT5 served as an adaptor for STAT3, displaying a dual inhibitory role on DDIT3 transcription to promote apoptosis resistance, and provided that its inhibitor HLCL-61 was an alternative therapeutic approach of HCC.