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From Epigenetic Dysregulation to Therapeutic Reprogramming in Endometrial Cancer: A State-Response Framework for

Manyata Srivastava1, Shishir Singh2, Pratik Kumar1

  • 1Translational Oncology & Women's Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India.

International Journal of Molecular Sciences
|May 27, 2026
PubMed

Insights

Epigenetic dysregulation impacts endometrial cancer (EC) treatment response. Targeting dynamic epigenetic states offers a strategy to overcome resistance and improve patient outcomes by reprogramming tumor behavior.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Endometrial cancer (EC) exhibits heterogeneity, leading to varied treatment responses and resistance.
  • Current treatments often fail due to a lack of understanding of dynamic regulatory mechanisms beyond static genomic alterations.
  • Epigenetic dysregulation (DNA methylation, histone modification, ncRNAs) dynamically governs tumor adaptation and therapeutic response.

Purpose of the Study:

  • To investigate the role of epigenetic dysregulation in endometrial cancer (EC) therapeutic response and resistance.
  • To establish an Epigenetic State-Response Framework (ESRF) linking epigenetic states to treatment sensitivity and resistance.
  • To explore epigenetic biomarkers and therapeutic strategies for improving EC treatment outcomes.

Main Methods:

  • Analysis of epigenetic alterations in key regulators (MLH1, PTEN, hormone receptors) in EC.
  • Evaluation of epigenetic states' influence on immune recognition, pathway activation, and cell cycle control.
  • Review of epigenetic biomarkers (methylation signatures, circulating RNAs) for patient stratification and monitoring.
  • Assessment of epigenetic therapies (DNMT and HDAC inhibitors) and emerging approaches (epigenetic editing, liquid biopsies).

Main Results:

  • Epigenetic alterations directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment in EC.
  • Dynamic epigenetic states shape response to chemotherapy and immune checkpoint blockade by affecting tumor biology.
  • Epigenetic biomarkers show potential for patient stratification and longitudinal treatment monitoring.
  • Epigenetic therapies, especially in combination, demonstrate potential to enhance treatment efficacy and reverse resistance.

Conclusions:

  • Epigenetics is a critical determinant of therapeutic behavior in EC, shifting from a descriptive feature to a modifiable target.
  • The proposed Epigenetic State-Response Framework (ESRF) integrates dynamic epigenetic states with treatment response and vulnerabilities.
  • Integrating epigenetic reprogramming into clinical decision-making is crucial for improving treatment response and overcoming resistance in EC.
Keywords:
DNA methylationHDAC inhibitorsendometrial cancerepigenetic reprogrammingimmunotherapy sensitizationtherapeutic resistancetreatment response

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