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Histone methyltransferase SETD2 regulates osteosarcoma cell growth and chemosensitivity by suppressing Wnt/β-catenin

Chaoyin Jiang1, Chao He2, Zhiqiang Wu3

  • 1Department of Bone Tumor Surgery, Changzheng Hospital, Second MilitaryMedical University, Shanghai, 200003, China.

Biochemical and Biophysical Research Communications
|May 30, 2018
PubMed

Insights

The study found that SETD2 (histone methyltransferase) inhibits osteosarcoma growth and enhances chemotherapy sensitivity. SETD2 regulates Wnt/β-catenin signaling, suggesting it as a potential diagnostic and therapeutic target for osteosarcoma.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • SETD2, a histone methyltransferase, catalyzes H3K36 trimethylation.
  • SETD2 mutations are common in human cancers, but its role in osteosarcoma is undefined.
  • Osteosarcoma (OS) is a primary bone cancer with limited treatment options.

Purpose of the Study:

  • To investigate the role of SETD2 in osteosarcoma (OS) oncogenesis.
  • To determine SETD2's impact on OS tumor growth and chemosensitivity.
  • To elucidate the molecular mechanisms by which SETD2 influences OS.

Main Methods:

  • In vitro and in vivo studies of osteosarcoma cell lines.
  • Assessment of apoptosis, cell growth, and cancer stem cell properties.
  • Analysis of Wnt/β-catenin signaling pathway components and downstream targets (c-myc, CD133, cyclin D1).
  • Chromatin immunoprecipitation (ChIP) to examine H3K36me3 modification at GSK3B loci.

Main Results:

  • SETD2 overexpression significantly inhibited osteosarcoma cell proliferation in vitro and in vivo.
  • SETD2 enhanced cisplatin-induced apoptosis and suppressed cancer stem cell characteristics in OS cells.
  • SETD2 was found to regulate Wnt/β-catenin signaling by upregulating H3K36me3 at GSK3B, promoting its transcription and leading to β-catenin degradation.

Conclusions:

  • SETD2 acts as a tumor suppressor in osteosarcoma.
  • SETD2 regulates osteosarcoma progression and chemosensitivity through the Wnt/β-catenin pathway.
  • SETD2 represents a novel therapeutic target for osteosarcoma diagnosis and combination chemotherapy.
Keywords:
Cancer stem cellChemosensitivityOsteosarcomaSETD2Wnt/β-catenin signaling

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