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Estrogen and progesterone are critically involved in the development of breast cancer and their effects are mediated by the estrogen receptor (ER) and progesterone receptor (PR) respectively. The activities of ER and PR are regulated at multiple steps of steroid hormone receptor (SHR) signaling pathway. Post-translational modifications (PTMs) play pivotal roles in regulating SHR signaling, enable quick responses of these receptors to stimuli without the need for new protein synthesis. Initial mass spectrometry analysis of PTMs on ER identified multiple methylated arginines, suggesting that arginine methylation is an important player regulating ER activity. The objectives of the first part of the thesis were to identify protein arginine methyltransferases (PRMTs) that methylate ER and PR and to determine the functional relevance of the methylation. This study showed that PRMT6 binds to ER, PR and androgen receptor (AR), and methylates them independent of ligand. The site of the interaction and mode of regulation by PRMT6 seems to vary among the receptors but the role of PRMT6 in regulating ER activity has been further defined. PRMT6 binds to ER at the C-terminus domains (LBO-region F) and proximity ligation assays indicated that PRMT6 interacts with ER exclusively in the nucleus. PRMT6 overexpression enhances ER ligand-independent and ligand-induced activity via different mechanisms. PRMT6 significantly enhances the ligand-independent activity of ER without the need for its methyltransferase activity. We present evidences suggesting that the ligand-independent activation of ER by PRMT6 is mediated through its binding to ER which may lead to dissociation of chaperone heat shock protein 70 (Hsp70) and Hsp90. On the other hand, enhancement of ligang-induced ER activity requires enzymatically active PRMT6 and possible arginine residues targeted by PRMT6 XI ATTENTION: The Singapore Copyright Act applies to the use of this document. Nanyang Technological University Library

Novel insight into the regulation of steroid hormone receptor signaling by protein arginine methyltransferase 6 and regulation of TRIM22 expression in breast cancer