Original Article

Oncogene (2017) 36, 373–386; doi:10.1038/onc.2016.205; published online 6 June 2016

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

H Chen1, B Lorton1, V Gupta2 and D Shechter1

  1. 1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
  2. 2Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA

Correspondence: H Chen or Dr D Shechter, Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, 10461 NY, USA. E-mail: hongshan.chen@einstein.yu.edu or david.shechter@einstein.yu.edu

Received 10 February 2016; Revised 13 April 2016; Accepted 29 April 2016
Advance online publication 6 June 2016

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Abstract

Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for transcriptional regulation promoting cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. RNA-Seq transcriptome analysis demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and Epithelial-to-mesenchymal transition (EMT) markers and to potentiate an epigenetic mechanism of the TGFβ response. We show that PRMT5-MEP50 activity both positively and negatively regulates expression of a wide range of genes. Exogenous TGFβ promotes EMT in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity. PRMT5 methylation of histone H3R2me1 induced transcriptional activation by recruitment of WDR5 and concomitant H3K4 methylation at targeted genes. In parallel, PRMT5 methylation of histone H4R3me2s suppressed transcription at distinct genomic loci. Our decoding of histone methylarginine at key genes supports a critical role for complementary PRMT5-MEP50 transcriptional activation and repression in cancer invasion pathways and in response to TGFβ stimulation and therefore orients future chemotherapeutic opportunities.