Isoform-Specific Lysine Methylation of RORα2 by SETD7 Is Required for Association of the TIP60 Coactivator Complex in Prostate Cancer Progression.

Hyerin Song,Il-Geun Park,Hyuntae Im,Jung Woong Chu,Su Chan Park,Hyunkyung Kim,Ji Min Lee

doi:10.3390/ijms21051622

Abstract

The retinoid acid-related orphan receptor α (RORα), a member of the orphan nuclear receptor superfamily, functions as an unknown ligand-dependent transcription factor. RORα 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 RORα gene encodes at least four distinct isoforms (RORα1, -2, -3, -4), which differ only in their N-terminal domain (NTD). Two isoforms, RORα2 and 3, are not expressed in mice, whereas RORα1 and 4 are expressed both in mice and humans. In the present study, we identified the specific NTD of RORα2 that enhances prostate tumor progression and proliferation via lysine methylation-mediated recruitment of coactivator complex pontin/Tip60. Upregulation of the RORα2 isoform in prostate cancers putatively promotes tumor formation and progression. Furthermore, binding between coactivator complex and RORα2 is increased by lysine methylation of RORα2 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 RORα2. Thus, post-translational lysine methylation of RORα2 modulates oncogenic function of RORα2 in prostate cancer. Exploration of the post-translational modifications of RORα2 provides new avenues for the development of tumor-suppressive therapeutic agents through modulating the human isoform-specific tumorigenic role of RORα2.

Highlights

Retinoid acid-related orphan receptor α (RORα) belongs to the nuclear receptor family 1 group F members (NR1F) and is classified as an orphan nuclear receptor because endogenous ligands are not yet determined [1,2,3]
To define the unknown roles of RORα2 isoform in Prostate cancer (PCa), we examined the expression of RORα2 in tumorigenesis experiments with prostate cells in athymic nude mice
We identified a specific oncogenic signaling downstream pathway of RORα2: lysine methylation modification of RORα2 in modulation of binding with coactivator complex and PCa cell growth and proliferation

Summary

Introduction

Retinoid acid-related orphan receptor α (RORα) belongs to the nuclear receptor family 1 group F members (NR1F) and is classified as an orphan nuclear receptor because endogenous ligands are not yet determined [1,2,3]. The messenger RNA (mRNA) and protein isoforms generated by alternative processing of primary RNA transcripts may differ in protein function, structure, localization, or other biological properties. By this alternative exon splicing of mRNA, the RORα gene generates four isoforms that have a common DNA-binding domain (DBD) and ligand-binding domain (LBD), but contain distinct N-terminal domains (NTDs) in humans [4,5]. Several studies revealed that the distinct NTD, which differs between the RORα isoforms, provides sites for coregulator binding and protein modification so that each isoform functions as a potent regulator to activate target gene expression under different physiological conditions

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