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Autonomous action and cooperativity between the ONECUT2 transcription factor and its 3' untranslated region

Kenneth Steadman1, Sungyong You1, Dustin V Srinivas1

  • 1Division of Cancer Biology and Therapeutics, Biomedical Sciences and Pathology and Laboratory Medicine, Department of Urology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, United States.

Frontiers in Cell and Developmental Biology
|July 24, 2023
PubMed

Insights

ONECUT2 (OC2) acts as both a transcription factor and a competing endogenous RNA (ceRNA) in prostate cancer. Its 3' UTR promotes metastasis and protects OC2-regulated genes from microRNA suppression, reinforcing tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • ONECUT2 (OC2) is a key regulator in metastatic castration-resistant prostate cancer, influencing androgen receptor activity, neural differentiation, and tumor cell survival.
  • OC2 mRNA has an exceptionally long 3' untranslated region (UTR) with numerous microRNA binding sites, including many for miR-9, which targets similar genes as OC2 protein.
  • The paradox of high OC2 and miR-9 expression suggests a regulatory mechanism beyond simple targeting.

Purpose of the Study:

  • To investigate the novel role of the OC2 3' UTR in lethal prostate cancer.
  • To explore the function of OC2 3' UTR as a competing endogenous RNA (ceRNA).
  • To elucidate the cooperative relationship between OC2 protein and its 3' UTR in regulating gene expression and promoting cancer progression.

Main Methods:

  • Computational construction of a ceRNA network involving OC2 3' UTR in OC2-driven tumors.
  • Experimental validation of the ceRNA network in prostate cancer cell lines.
  • In vitro assays to assess the metastatic potential conferred by OC2 3' UTR expression.

Main Results:

  • A functional ceRNA network for OC2 3' UTR was identified and confirmed.
  • Genes regulated by OC2 3' UTR significantly overlapped with those regulated by OC2 protein, indicating a cooperative function.
  • OC2 3' UTR expression alone dramatically increased metastatic potential and altered androgen synthesis pathway genes (Aldo-Keto reductase, UDP-glucuronyl transferase).

Conclusions:

  • OC2 3' UTR functions as a master ceRNA, sequestering miRNAs and protecting OC2-regulated mRNAs from suppression.
  • The OC2 protein and its 3' UTR exhibit cooperative activity, reinforcing OC2-driven transcriptional networks and promoting castration-resistant prostate cancer.
  • ONECUT2 is a unique dual-modality transcript, acting as both a critical transcription factor and a master ceRNA in prostate cancer progression.
Keywords:
androgen metabolismcompetitive endogenous RNA networkneuroendocrine prostate cancerpolycomb repressing complexprostate cancer

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