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HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells

Suchitra Natarajan1, Sabine Hombach-Klonisch, Peter Dröge

  • 1Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.

Neoplasia (New York, N.Y.)
|March 13, 2013
PubMed

Insights

High mobility group AT-hook 2 (HMGA2) protein enhances DNA repair in cancer cells by activating the ATR-CHK1 pathway. This finding suggests HMGA2 and ATR/CHK1 inhibitors could be effective cancer treatments.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • High mobility group AT-hook 2 (HMGA2) is a non-histone chromatin protein found in stem and cancer cells, but not normal somatic cells.
  • HMGA2 expression correlates with advanced cancer and poor patient prognosis, and has a previously identified role in DNA repair.
  • Its role in cancer cell DNA damage response pathways remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of HMGA2 in DNA damage response pathways in human tumor cells.
  • To elucidate the relationship between HMGA2 and the ataxia telangiectasia and Rad3-related kinase (ATR)-checkpoint kinase 1 (CHK1) pathway.
  • To determine the impact of HMGA2 on DNA damage-induced cell cycle arrest and survival.

Main Methods:

  • Utilized human tumor cell models with varying HMGA2 expression (endogenous and exogenous).
  • Induced DNA damage to observe cellular responses.
  • Assessed phosphorylation of ATR and CHK1, cell cycle progression (G2/M block), and tumor cell survival.

Main Results:

  • HMGA2 presence led to increased and sustained phosphorylation of ATR and its downstream target CHK1 upon DNA damage.
  • Activated pCHK1 (Ser296) correlated with prolonged G2/M cell cycle arrest.
  • HMGA2 further enhanced tumor cell survival following DNA damage.

Conclusions:

  • Identified a novel link between the ATR-CHK1 DNA damage response pathway and HMGA2 in cancer cells.
  • HMGA2 may support DNA repair functions in cancer cells via this pathway.
  • These findings support the potential use of ATR, CHK1, and HMGA2 inhibitors for treating HMGA2-positive cancers.

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