title: Protein arginine methyltransferase 6 enhances ligand-dependent and -independent activity of estrogen receptor α via distinct mechanisms.
abstract: Recent studies reported that protein arginine methyltransferase 6 (PRMT6) enhances estrogen-induced activity of estrogen receptor α (ERα) and dysfunction of PRMT6 is associated with overall better survival for ERα-positive breast cancer patients. However, it is unclear how PRMT6 promotes ERα activity. Here we report that PRMT6 specifically interacts with ERα at its ligand-binding domain. PRMT6 also methylates ERα both in vitro and in vivo. In addition to enhancing estrogen-induced ERα activity, PRMT6 over-expression up-regulates estrogen-independent activity of ERα and PRMT6 gene silencing in MCF7 cells inhibits ligand-independent ERα activation. More interestingly, the effect of PRMT6 on the ligand-independent ERα activity does not require its methyltransferase activity. Instead, PRMT6 competes with Hsp90 for ERα binding: PRMT6 and Hsp90 bindings to ERα are mutually exclusive and PRMT6 over-expression reduces ERα interaction with Hsp90. In conclusion, PRMT6 requires its methyltransferase activity to enhance ERα's ligand-induced activity, but its effect on ligand-independent activity is likely mediated through competing with Hsp90 for binding to the C-terminal domain of ERα. PRMT6-ERα interaction would prevent ERα-Hsp90 association. Since Hsp90 and associated chaperones serve to maintain ERα conformation for ligand-binding yet functionally inactive, inhibition of ERα-Hsp90 interaction would relieve ERα from the constraint of chaperone complex.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Hwa Hwa
authors.initials: HH
authors.lastname: Chung
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Amanda Rui En
authors.initials: AR
authors.lastname: Woo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore. Electronic address: cllin@ntu.edu.sg.
authors.forename: Valerie C-L
authors.initials: VC
authors.lastname: Lin
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008745:Methylation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases; D019061:src-Family Kinases
keywords: Breast cancer; Chaperone binding; Hsp90; Steroid hormone receptor