TY - JOUR
T1 - Isoform‐specific lysine methylation of RORα2 by SETD7 is required for association of the TIP60 coactivator complex in prostate cancer progression
AU - Song, Hyerin
AU - Chu, Jung Woong
AU - Park, Su Chan
AU - Im, Hyuntae
AU - Park, Il Geun
AU - Kim, Hyunkyung
AU - Lee, Ji Min
N1 - Funding Information:
This work was supported by the Basic Science Research Program (NRF- 2018R1D1A1A02085592) to J.M.L. by the National Research Foundation (NRF) grant funded by the Korea government, 2019 Research Grant from Kangwon National University to J.M.L, and by a Korea University Medical Center Grant to H.K.
Funding Information:
Funding: This work was supported by the Basic Science Research Program (NRF‐ 2018R1D1A1A02085592) to J.M.L. by the National Research Foundation (NRF) grant funded by the Korea government, 2019 Research Grant from Kangwon National University to J.M.L, and by a Korea University Medical Center Grant to H.K.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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 antiapoptosis. 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.
AB - 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 antiapoptosis. 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.
KW - Lysine methylation
KW - N‐terminal domain
KW - Oncogene
KW - Prostate cancer
KW - RORα2
UR - http://www.scopus.com/inward/record.url?scp=85080854442&partnerID=8YFLogxK
U2 - 10.3390/ijms21051622
DO - 10.3390/ijms21051622
M3 - Article
C2 - 32120841
AN - SCOPUS:85080854442
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 5
M1 - 1622
ER -