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CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer

Mengjiao Han1, Dongjun Dai1, Neelum Aziz Yousafzai1

  • 1Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.

Oncotarget
|December 22, 2017
PubMed

Insights

Nuclear protein CXXC4 acts as a tumor suppressor in gastric cancer by inducing apoptosis. It up-regulates Growth Differentiation Factor 15 (GDF15), a potential therapeutic target for gastric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Gastric cancer is a leading cause of cancer mortality globally.
  • Epigenetic modifications are crucial in gastric cancer pathogenesis, often silencing tumor suppressor genes.
  • CXXC finger protein 4 (CXXC4) was previously identified as a novel tumor suppressor in gastric cancer.

Purpose of the Study:

  • To elucidate the mechanism by which CXXC4 functions as a tumor suppressor in gastric cancer.
  • To investigate the role of CXXC4 in apoptosis induction and identify its downstream targets.
  • To explore the therapeutic potential of targeting CXXC4 or its downstream effectors.

Main Methods:

  • Cell-based assays to assess CXXC4's effect on gastric cancer cell growth and apoptosis.
  • Use of pan-caspase inhibitor Z-VAD-FMK to confirm caspase-dependent apoptosis.
  • Mutation analysis of CXXC4's DNA binding domain to assess its role in apoptosis induction.
  • Reporter assays and chromatin immunoprecipitation to identify and validate GDF15 as a downstream target and elucidate the transcriptional regulation mechanism.

Main Results:

  • CXXC4 significantly inhibited gastric cancer cell growth by acting as a pro-apoptotic factor.
  • The pro-apoptotic effect of CXXC4 was dependent on caspase activity and the integrity of its DNA binding domain.
  • Growth differentiation factor 15 (GDF15) was identified as a key downstream target, with CXXC4 enhancing GDF15 transcription via Sp1 interaction with the GDF15 promoter.

Conclusions:

  • CXXC4 induces apoptosis in gastric cancer cells through up-regulation of its novel downstream target, GDF15.
  • GDF15 represents a promising therapeutic target for gastric cancer, particularly in cases with CXXC4 deficiency.
Keywords:
CXXC4GDF15apoptosisgastric cancer

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