Isoform-Specific Lysine Methylation of ROR alpha 2 by SETD7 Is Required for Association of the TIP60 Coactivator Complex in Prostate Cancer Progression

Abstract

The retinoid acid-related orphan receptor alpha (ROR alpha), a member of the orphan nuclear receptor superfamily, functions as an unknown ligand-dependent transcription factor. ROR alpha was shown to regulate a broad array of physiological processes such as Purkinje cell development in the cerebellum, circadian rhythm, lipid and bone metabolism, inhibition of inflammation, and anti-apoptosis. The human ROR alpha gene encodes at least four distinct isoforms (ROR alpha 1, -2, -3, -4), which differ only in their N-terminal domain (NTD). Two isoforms, ROR alpha 2 and 3, are not expressed in mice, whereas ROR alpha 1 and 4 are expressed both in mice and humans. In the present study, we identified the specific NTD of ROR alpha 2 that enhances prostate tumor progression and proliferation via lysine methylation-mediated recruitment of coactivator complex pontin/Tip60. Upregulation of the ROR alpha 2 isoform in prostate cancers putatively promotes tumor formation and progression. Furthermore, binding between coactivator complex and ROR alpha 2 is increased by lysine methylation of ROR alpha 2 because methylation permits subsequent interaction with binding partners. This methylation-dependent activation is performed by SET domain containing 7 (SETD7) methyltransferase, inducing the oncogenic potential of ROR alpha 2. Thus, post-translational lysine methylation of ROR alpha 2 modulates oncogenic function of ROR alpha 2 in prostate cancer. Exploration of the post-translational modifications of ROR alpha 2 provides new avenues for the development of tumor-suppressive therapeutic agents through modulating the human isoform-specific tumorigenic role of ROR alpha 2.