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HIC1 interacts with and modulates the activity of STAT3

Ying-Mei Lin1, Chia-Mei Wang, Jen-Chong Jeng

  • 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.

Cell Cycle (Georgetown, Tex.)
|September 27, 2013
PubMed

Insights

Hypermethylated in cancer 1 (HIC1) suppresses tumor growth by inhibiting signal transducer and activator of transcription 3 (STAT3). HIC1 antagonizes STAT3

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Gene Regulation

Background:

  • Hypermethylated in cancer 1 (HIC1) is a tumor suppressor gene with largely unknown mechanisms of action in cancer.
  • Oncogenic pathways, such as those involving signal transducer and activator of transcription 3 (STAT3), are frequently activated in human cancers.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which HIC1 antagonizes oncogenic pathways.
  • To investigate the interaction between HIC1 and STAT3 and its functional consequences.

Main Methods:

  • Affinity capture and mass spectrometry to identify HIC1-interacting proteins.
  • Reporter gene assays to assess STAT3-mediated transcription.
  • Quantitative PCR and Western blotting to measure gene expression.
  • Cell proliferation assays (colony formation).
  • Domain mapping and mutagenesis studies.

Main Results:

  • HIC1 directly interacts with STAT3, specifically binding to its DNA binding domain.
  • HIC1 suppresses STAT3-mediated transcription of target genes, including VEGF and c-Myc.
  • HIC1 inhibits IL-6/OSM-induced STAT3 activity, reporter gene expression, and target gene expression.
  • HIC1's suppression of VEGF and c-Myc promoter activity and MDA-MB 231 cell growth is STAT3-dependent.
  • A HIC1 mutant unable to bind STAT3 loses its repressive effects on STAT3 activity and cell growth.

Conclusions:

  • HIC1 acts as a novel inhibitor of STAT3 transcriptional activity.
  • HIC1 antagonizes STAT3-mediated activation of VEGF and c-Myc, thereby suppressing cell growth.
  • The C-terminal domain of HIC1 is crucial for STAT3 interaction and tumor suppressor function.
Keywords:
DNA bindingHIC1STAT3protein interactiontranscriptional regulation

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