PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis

Abstract

Background: Protein arginine methyltransferase 4 (PRMT4) has been reported to play a role in several common cancers; however, the function and mechanism of PRMT4 in hepatocellular carcinoma (HCC) are not fully understood. This study aimed to investigate the role and mechanism of PRMT4 in the progression of HCC. Methods: PRMT4 expression and clinicopathological characteristics were investigated using an HCC tissue microarray (TMA) consisting of 140 patient samples analyzed by immunohistochemistry. CCK-8, crystal violet and Transwell assays were used to determine cell proliferation, colony formation, migration, and invasion of HCC cell lines in which PRMT4 was overexpressed or downregulated. The underlying mechanism of PRMT4 function was explored by Western blot assays. Results: PRMT4 was highly expressed in HCC tumor tissues compared to adjacent nontumor tissues. PRMT4 expression was significantly associated with alpha-fetoprotein levels, tumor size, satellite nodules, and microvascular invasion. Patients with higher PRMT4 expression had a shorter survival time and higher recurrence rate. Functional studies demonstrated that PRMT4 overexpression promoted HCC cell proliferation, migration, and invasion in vitro, while knocking down PRMT4 inhibited these malignant behaviors. Additional results revealed that PRMT4 promoted the progression of HCC cells via activation of the AKT/mTOR signaling pathway. Furthermore, inhibition of the AKT/mTOR signaling by MK2206 or rapamycin significantly attenuated PRMT4-mediated malignant phenotypes. Conclusions: This study suggests that PRMT4 may promote the progression of HCC cells by activating the AKT/mTOR signaling pathway, which may be a valuable biomarker and potential target for HCC.

Arginine Methylation-dependent TRIM47 Stability Mediated by CARM1 Promotes the Metastasis of Hepatocellular Carcinoma

“…CARM1 was previously reported to suppress the glycolysis in liver cancer cells by mediating arginine 234 (R234) methylation of GAPDH, thus inhibiting the proliferation of liver cancer cells 12 . This con icts with another study demonstrating that CARM1 indicates poor prognosis and promotes HCC progression by activating AKT/mTOR signaling 13 . These con icting results lead to a confused understanding of CARM1's functions in HCC, thus needing to explore its underlying molecular mechanism.…”

“…CARM1 functions as an oncogene or a tumor suppressor depending on cancer types 16,17 . However, the roles of CARM1 in dynamic HCC progression are controversial 12,13 . We analyzed the HCC cohort in TCGA and found that HCC patients at the advanced stages expressed higher CARM1 than early staged patients (stage III + IV vs stage I + II) (Fig.…”

Arginine methylation of PPP1CA by CARM1 regulates glucose metabolism and affects osteogenic differentiation and osteoclastic differentiation

“…revealed proteins that can interact directly with CARM1 and proteins with arginine methylation sites, but PFK1 and PFKFB3 were not among these proteins. AKT and AMPK are able to activate PFK1 and PFKFB3 when they exert kinase activity, 22,39,40 and both kinases can be regulated by CARM1 41,42 . To decipher the molecular mechanisms by which CARM1 regulates cellular metabolism, transcriptomic assays were performed on Carm1 ‐OE MC3T3E1 cells (Figure S4a), and the results showed that the osteogenesis‐related genes Spp1 and Ocn and several members of the Col1 family had up‐regulated expression in the Carm1 ‐OE group.…”

“…AKT and AMPK are able to activate PFK1 and PFKFB3 when they exert kinase activity, 22 , 39 , 40 and both kinases can be regulated by CARM1. 41 , 42 To decipher the molecular mechanisms by which CARM1 regulates cellular metabolism, transcriptomic assays were performed on Carm1 ‐OE MC3T3E1 cells (Figure S4a ), and the results showed that the osteogenesis‐related genes Spp1 and Ocn and several members of the Col1 family had up‐regulated expression in the Carm1 ‐OE group. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PI3K–AKT signalling pathway was one of the main enriched pathways with differentially expressed genes (Figure 4a ).…”

PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis: Erratum

“…The original version of our article 1 unfortunately contained an error in Figure 3 E. The picture of Huh7 cell invasion assay picture in the sh2 group in Figure 3 E was incorrectly assembled. We sincerely apologize for this error.…”