Article published by the Endocrine Society Article published by the Endocrine Society

Protein arginine methylation/demethylation and cancer

PRMT1, the major protein arginine methyltransferase in mammals, catalyzes monomethylation and asymmetric dimethylation of arginine side chains in proteins. Initially described as a regulator of chromatin dynamics through the methylation of histone H4 at arginine 3 (H4R3), numerous non-histone substrates have since been identified. The variety of these substrates underlines the essential role played by PRMT1 in a large number of biological processes such as transcriptional regulation, signal transduction or DNA repair. This review will provide an overview of the structural, biochemical and cellular features of PRMT1. After a description of the genomic organization and protein structure of PRMT1, special consideration was given to the regulation of PRMT1 enzymatic activity. Finally, we discuss the involvement of PRMT1 in embryonic development, DNA damage repair, as well as its participation in the initiation and progression of several types of cancers.

ERα functions are tightly controlled by numerous post-translational modifications including arginine methylation, which is required to mediate the extranuclear functions of the receptor. We report that upon oestrogenic stimulation, JMJD6, the only arginine demethylase described so far, interacts with and regulates methylated ERα (metERα) function. Moreover, by combining the silencing of JMJD6 with demethylation assays, we show that metERα is a new substrate for JMJD6. We propose that the demethylase activity of JMJD6 is a decisive regulator of the rapid physiological responses to oestrogen.

Oestrogen receptors can mediate rapid activation of cytoplasmic signalling cascades by recruiting Src and PI3K. However, the involvement of this pathway in breast cancer remains poorly defined. We have previously shown that methylation of ERα is required for the formation of the ERα/Src/PI3K complex and that ERα is hypermethylated in a subset of breast cancers. Here, we used Proximity Ligation Assay to demonstrate that this complex is present in the cytoplasm of breast cancer cell lines as well as formalin‐fixed, paraffin‐embedded tumours. Of particular interest, the analysis of 175 breast tumours showed that overexpression of this complex in a subset of breast tumours correlates to the activation of the downstream effector Akt. Survival analysis revealed that high expression of this complex is an independent marker of poor prognosis and associated with reduced disease‐free survival. Our data introduces the new concept that the rapid oestrogen pathway is operative in vivo . It also provides a rationale for patient stratification defined by the activation of this pathway and the identification of target therapies.

Protein arginine methylation is a common post translational modification that regulates protein properties. This modification is carried out by a family of nine arginine methyltransferases (PRMTs). Arginine methylation has already been linked to tumourigenesis as overexpression of these enzymes was associated with various cancers, notably in breast cancers. Since the Jumonji Domain Containing 6 protein (JMJD6) possesses an arginine demethylase activity able to remove the methyl mark, we wanted to assess its potential role in breast tumourigenesis. The expression of the protein by tissue microarray immunohistochemical staining was performed on a cohort of 133 breast tumours. Using cell lines stably overexpressing or knocked down for JMJD6, we evaluated its role on cell proliferation, cell migration, colony formation and mice tumour xenografts. The analysis of JMJD6 expression in a cohort of breast tumour samples indicates that JMJD6 was highly expressed in aggressive breast tumours. Moreover, high expression of JMJD6 was associated with poor disease-free survival of patients in this cohort. JMJD6 silencing in breast tumoural cells promotes certain characteristics of tumourigenesis including proliferation, migration in vitro, and tumour growth in vivo. These effects are dependent on its demethylase activity as an enzymatic dead mutant lost these properties. Although JMJD6 displays anti-tumoral properties in cell lines, its expression in breast tumours may be a marker of poor prognosis, suggesting that its function could be altered in breast cancer.