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RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression

Srinivasa P Kolapalli1, Rinku Sahu1, Nishant R Chauhan1

  • 1Cell and Cancer Biology Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Cancer Research
|October 17, 2020
PubMed

Insights

The study reveals DZIP3 (Developmental Zest Interacting Protein 3) drives cancer progression by stabilizing Cyclin D1 mRNA and protein. This dual mechanism promotes cell growth, migration, and metastasis in various cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • DZIP3 (Developmental Zest Interacting Protein 3), also known as hRUL138, is an RNA-binding RING E3-ubiquitin ligase with known roles in embryonic development.
  • Its precise role in cancer progression, particularly its molecular mechanisms, remains poorly understood.
  • Cyclin D1 is a key regulator of the G1 phase of the cell cycle and is frequently dysregulated in cancer.

Purpose of the Study:

  • To investigate the role of DZIP3 in driving cancer cell growth, migration, and invasion.
  • To elucidate the molecular mechanisms by which DZIP3 influences cancer progression, focusing on its interaction with Cyclin D1.
  • To determine if DZIP3 overexpression correlates with cancer types and patient outcomes.

Main Methods:

  • Utilized mouse and zebrafish cancer models to assess the impact of DZIP3 on tumor growth and metastasis.
  • Employed cell depletion experiments to analyze the effects of DZIP3 loss on cell cycle progression and gene expression.
  • Investigated DZIP3's molecular interactions with Cyclin D1 mRNA and protein using RNA-binding and ubiquitination assays, including cell cycle phase-specific analysis.

Main Results:

  • DZIP3 significantly promotes tumor growth and metastasis in preclinical cancer models.
  • DZIP3 overexpression is frequent in various human cancer types and correlates with Cyclin D1 expression.
  • DZIP3 depletion causes G1 cell cycle arrest by reducing Cyclin D1 levels, achieved through stabilizing Cyclin D1 mRNA via its RNA-binding domain and stabilizing Cyclin D1 protein via its E3-ligase domain, predominantly in G1 phase.

Conclusions:

  • DZIP3 is a critical driver of cancer progression, acting as a novel oncogene.
  • DZIP3 employs a unique dual mechanism to stabilize Cyclin D1 at both mRNA and protein levels in a cell-cycle-dependent manner, thereby promoting cell proliferation and cancer.
  • These findings highlight DZIP3 as a potential therapeutic target for various cancers.

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