PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma

Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, has roles in cell growth regulation and cancer development. However, the role of PRMT5 in hepatocellular carcinoma (HCC) progression remains unclear. Here, we showed that PRMT5 expression was frequently upregulated in HCC tissues, and its expression was inversely correlated with overall survival in HCC patients. PRMT5 knockdown markedly inhibited in vitro HCC proliferation and in vivo tumorigenesis. We revealed that the mechanism of PRMT5‐induced proliferation was partially mediated by BTG downregulation, leading to cell cycle arrest during the G1 phase in HCC cells. Ectopic BTG2 overexpression decreased HCC growth, caused cell cycle arrest at the G1 phase, and downregulated Cyclin D1 and Cyclin E1 protein expression. Furthermore, we found that PRMT5‐induced ERK phosphorylation regulated BTG2 expression in HCC cells, whereas pretreatment with a selective ERK1/2 inhibitor (PD184352) significantly reversed the effect of PRMT5 on BTG2 expression. Our results indicated that PRMT5 promotes HCC proliferation by downregulating BTG2 expression via the ERK pathway.

[1]  Nam-Soon Kim,et al.  Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  A. Imbalzano,et al.  The expression of myogenic microRNAs indirectly requires protein arginine methyltransferase (Prmt)5 but directly requires Prmt4 , 2010, Nucleic acids research.

[3]  I. Ng,et al.  Molecular Pathogenesis of Hepatocellular Carcinoma. , 2016, Liver cancer.

[4]  A. Imbalzano,et al.  Distinct Protein Arginine Methyltransferases Promote ATP-Dependent Chromatin Remodeling Function at Different Stages of Skeletal Muscle Differentiation , 2009, Molecular and Cellular Biology.

[5]  Sharmistha Pal,et al.  Low levels of miR‐92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma , 2007, The EMBO journal.

[6]  Sharmistha Pal,et al.  The Protein Arginine Methyltransferase Prmt5 Is Required for Myogenesis because It Facilitates ATP-Dependent Chromatin Remodeling , 2006, Molecular and Cellular Biology.

[7]  H. Zhang,et al.  Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth , 2016, Oncogene.

[8]  X. Cen,et al.  Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3 , 2015, Oncotarget.

[9]  Sharmistha Pal,et al.  Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells , 2008, Molecular and Cellular Biology.

[10]  E. Choi,et al.  Pathological roles of MAPK signaling pathways in human diseases. , 2010, Biochimica et biophysica acta.

[11]  B. Niu,et al.  Overexpression of Aurora-A Enhances Invasion and Matrix Metalloproteinase-2 Expression in Esophageal Squamous Cell Carcinoma Cells , 2012, Molecular Cancer Research.

[12]  A. Jemal,et al.  Cancer statistics in China, 2015 , 2016, CA: a cancer journal for clinicians.

[13]  Li-Jen Su,et al.  Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin‐dependent kinases and the phosphoinositide 3‐kinase/AKT signaling cascade , 2012, Cancer science.

[14]  Ying Yan,et al.  BRCA1-mediated G2/M cell cycle arrest requires ERK1/2 kinase activation , 2005, Oncogene.

[15]  Sharmistha Pal,et al.  Human SWI/SNF-Associated PRMT5 Methylates Histone H3 Arginine 8 and Negatively Regulates Expression of ST7 and NM23 Tumor Suppressor Genes , 2004, Molecular and Cellular Biology.

[16]  Jianwen Liu,et al.  MiR-27a-3p functions as an oncogene in gastric cancer by targeting BTG2 , 2016, Oncotarget.

[17]  S. Matsuda,et al.  In search of a function for the TIS21/PC3/BTG1/TOB family , 2001, FEBS letters.

[18]  H. Baik,et al.  Melatonin inhibits human fibroblast‐like synoviocyte proliferation via extracellular signal‐regulated protein kinase/P21CIP1/P27KIP1 pathways , 2009, Journal of pineal research.

[19]  H. Wang,et al.  TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1–Forkhead box M1 regulation loop , 2008, Hepatology.

[20]  G. Merlino,et al.  Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF , 2011, Science Signaling.

[21]  S. Ishii,et al.  Ski co‐repressor complexes maintain the basal repressed state of the TGF‐β target gene, SMAD7, via HDAC3 and PRMT5 , 2009, Genes to cells : devoted to molecular & cellular mechanisms.

[22]  D. Shechter,et al.  A TGFβ-PRMT5-MEP50 Axis Regulates Cancer Cell Invasion through Histone H3 and H4 Arginine Methylation Coupled Transcriptional Activation and Repression , 2016, Oncogene.

[23]  X. Cen,et al.  Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin , 2015, Journal of Translational Medicine.

[24]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[25]  Tsui-hsia Feng,et al.  Upregulation of B-cell translocation gene 2 by epigallocatechin-3-gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells. , 2015, Cancer letters.

[26]  I. Ng,et al.  Molecular Pathogenesis of Hepatocellular Carcinoma , 2016, Liver Cancer.

[27]  K. Tsui,et al.  Prostate-derived ets factor represses tumorigenesis and modulates epithelial-to-mesenchymal transition in bladder carcinoma cells. , 2016, Cancer letters.

[28]  R. Koski,et al.  Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. , 1991, The Journal of biological chemistry.

[29]  N. Holbrook,et al.  Requirement for ERK Activation in Cisplatin-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[30]  F. Feo,et al.  Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis. , 2013, Journal of hepatology.

[31]  Xinbin Chen,et al.  PRMT5 is required for cell-cycle progression and p53 tumor suppressor function , 2009, Nucleic acids research.

[32]  Ben S. Wittner,et al.  Supplementary Information Supplementary Figures , 2022 .

[33]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.

[34]  E. Shooter,et al.  Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Mak,et al.  ERK Activation Mediates Cell Cycle Arrest and Apoptosis after DNA Damage Independently of p53* , 2002, The Journal of Biological Chemistry.

[36]  P. Cohen,et al.  Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. , 1992, The Biochemical journal.

[37]  M. Kanda,et al.  Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer. , 2016, International journal of oncology.

[38]  Rajagopal N. Aravalli,et al.  Molecular mechanisms of hepatocellular carcinoma , 2008, Hepatology.