Protein Arginine Methyltransferase 5 Promotes Esophageal Squamous Cell Carcinoma Proliferation and Metastasis via LKB1/AMPK/mTOR Signaling Pathway

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer in the world. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes symmetric and asymmetric methylation on arginine residues of histone and non-histone proteins, is overexpressed in many cancers. However, whether or not PRMT5 participates in the regulation of ESCC remains largely unclear.Methods: PRMT5 mRNA and protein expression in ESCC tissues and cell lines were examined by RT-PCR, western blotting, and immunohistochemistry assays. Cell proliferation was examined by RT-PCR, western blotting, immunohistochemistry assays, MTT, and EdU assays. Cell apoptosis and cell cycle were examined by RT-PCR, western blotting, immunohistochemistry assays, and flow cytometry. Cell migration and invasion were examined by RT-PCR, western blotting, immunohistochemistry assays, and wound-healing and transwell assays. Tumor volume, tumors, and mouse weight were measured in different groups. Lung tissues with metastatic foci, the number of nodules, and lung/total weight were measured in different groups.Results: In the present study, the PRMT5 expression level was dramatically upregulated in ESCC clinical tissues as well as ESCC cell lines (ECA109 and KYSE150). Furthermore, knocking down PRMT5 obviously suppressed cell migration, invasion, proliferation, and cell arrest in G1 phase and promoted cell apoptosis in ESCC cells. Meanwhile, downregulating PRMT5 also increased the expression levels of Bax, caspase-3, and caspase-9, while expression levels of Bax-2, MMP-2, MMP-9, and p21 were decreased, which are members of the cyclin-dependent kinase family. Furthermore, knocking down PRMT5 could increase the expression of LKB1 and the phosphorylation (p)-AMPK expression and decrease the p-mTOR level. Additionally, overexpression of LKB1 could reveal anti-tumor effects in ESCC cell lines by inhibiting ESCC cell, migration, invasion, and proliferation and accelerating cell apoptosis. Besides, upregulating LKB1 expression could increase the levels of Bax, caspase-3, and caspase-9 and weaken the levels of Bax-2, MMP-2, and MMP-9. Moreover, knocking down PRMT5 could weaken the tumor growth and lung metastasis in vivo with upregulating the LKB1 expression and the p-AMPK level and downregulating the p-mTOR expression.Conclusion: PRMT5 may act as a tumor-inducing agent in ESCC by modulating LKB1/AMPK/mTOR pathway signaling.

STC2 activates PRMT5 to induce radioresistance through DNA damage repair and ferroptosis pathways in esophageal squamous cell carcinoma

“…We also found that regulated PRMT5 inhibited the expression of SLC7A11 in STC2-overexpressed cells, resulting in the accumulation of lipid peroxidation and ferroptosis. The documented evidence and our results [ 47 , 63 ] indicate that inhibition of PRMT5-ATF4-SLC3A2/SLC7A11 axis regulated by STC2 leads to radiosensitization in ESCC.…”

“…In this study, we observed that changes in the expression level of STC2 could affect the PRMT5 activity by regulating H4R3me2s. Many studies emphasized that PRMT5 was up-regulated in multiple cancer types, including ESCC, and was associated with poor prognosis [ [45] , [46] , [47] , [48] ]. Also, emerging evidence suggests that PRMT5 is a critical regulator of cellular proliferation, apoptosis, migration, cell cycle progression, cell metabolism, DNA damage response, and cell death [ [49] , [50] , [51] , [52] , [53] , [54] ].…”

Protein Arginine Methyltransferase 5 Functions via Interacting Proteins

“…In addition, the knock-down of PRMT5 could inhibit tumor growth and lung metastasis by the upregulation of LKB1 and p-AMPK, and the down-regulation of p-mTOR. PRMT5 may act as a tumor inducer in esophageal squamous cell carcinoma by regulating the LKB1/AMPK/mTOR signaling pathway (Chen et al, 2021). Epithelial-mesenchymal transition (EMT) is an important process triggered during cancer metastasis.…”

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway

“…The AMPK/mTOR signaling pathway is participated in apoptosis (Xie et al, 2022) and cell proliferation (Chen et al, 2021). The effect of VDAC1 on AMPK/mTOR signaling pathway was assessed.…”