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HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

D Palmieri1, T Valentino, D D'Angelo

  • 1Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy.

Oncogene
|February 23, 2011
PubMed

Insights

High-mobility group A (HMGA) proteins regulate ATM gene expression, impacting DNA damage response. Inhibiting HMGA enhances cancer cells

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • DNA-damaging therapies are crucial for cancer treatment but face resistance from specific cancer cell populations.
  • High-mobility group A (HMGA) proteins are implicated in cell transformation and are overexpressed in many cancers, correlating with poor prognosis and drug resistance.
  • Ataxia-telangiectasia mutated (ATM) is the primary cellular sensor of genotoxic stress.

Purpose of the Study:

  • To investigate the relationship between HMGA proteins and ATM in the context of DNA damage response.
  • To explore the role of HMGA proteins in regulating ATM gene expression and its impact on cancer drug resistance.

Main Methods:

  • Investigated HMGA1 and HMGA2 as substrates of ATM.
  • Analyzed HMGA proteins' effect on ATM gene expression using promoter activity assays.
  • Studied the impact of HMGA inhibition on ATM levels, DNA damage response, and sensitivity to DNA-damaging agents in cell models.

Main Results:

  • HMGA2 was identified as a novel substrate of ATM.
  • HMGA proteins positively regulate ATM gene expression, forming a positive feedback loop modulated by DNA damage and ATM activity.
  • Inhibition of HMGA expression reduced ATM protein levels, impaired DNA damage response, and increased sensitivity to DNA-damaging agents.

Conclusions:

  • A novel HMGA-ATM pathway has been identified, crucial for regulating the DNA damage response.
  • This pathway represents a potential therapeutic target to overcome resistance to genotoxic anti-cancer drugs.
  • Targeting HMGA could enhance the efficacy of conventional cancer treatments in resistant tumors.

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