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

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.

A Systematic Review to Define the Multi-Faceted Role of Lysine Methyltransferase SETD7 in Cancer

“…ROR-α2 K87R significantly decreased CTNND1 mRNA as compared to ROR-α2 WT and resulted in failure to increase PC-3 cell proliferation and viability. These suggests that SETD7 methylation of RORα2 promotes the recruitment of coactivator complex pontin/Tip60 to ROR-α2 target genes to support ROR-α2 oncogenic potential [75] (Figure 7). Another group published three papers in which they performed SETD7 knockdown in PCa cells [76][77][78] but only analysed the functional consequences in one of them [77].…”

“…Cellular processes regulated by SETD7 in prostate cancer where it functions as a tumour promoter. SETD7 methylates ROR-alpha2 promoting its binding with TIP60 to induce CTNND1 expression and proliferation [75]. SETD7 can also promote proliferation by methylating to enhance its transcriptional activity.…”

SETD7 mediates the vascular invasion in articular cartilage and chondrocytes apoptosis in osteoarthriis

“…Among these methylases, SETD7 can regulate the growth of blood vessels in the retina 9 and inhibit the activity of chondrocytes 10 . In addition, some studies have confirmed that SETD7 is associated with the inflammatory response and apoptosis induced by cytokines 11,12 . Consequently, we hypothesized that SETD7 may be a key molecule that links inflammation, angiogenesis, and chondrocyte apoptosis.…”

Pan‐cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer

“…We found that hypermethylation‐mediated downregulation of RORA was associated with poor survival in KIRC, suggesting that hypermethylated RORA might be a driver gene in that cancer. Numerous studies have reported that hypermethylation of RORA is associated with the progression of various cancers 36‐39 . However, there was also nonconformity among methylation, expression, and prognosis.…”