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ATP2B4 driven chromatin compaction exacerbates pancreatic cancer radiotherapy resistance

Yuyu Luo1,2, Wei Jiang1,3, Yanfang Liu1,2

  • 1Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China.

Cell Death Discovery
|May 25, 2026
PubMed

Insights

Pancreatic cancer

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Pancreatic cancer exhibits intrinsic radio-resistance, limiting treatment effectiveness.
  • The molecular basis for this radio-resistance is not fully understood.
  • Identifying novel targets is crucial for improving radiotherapy outcomes.

Purpose of the Study:

  • To identify novel molecular mechanisms contributing to radio-resistance in pancreatic cancer.
  • To investigate the role of ATPase Plasma Membrane Ca2+ Transporting 4 (ATP2B4) in radiotherapy resistance.
  • To explore ATP2B4 as a potential therapeutic target and biomarker.

Main Methods:

  • High-throughput metabolic CRISPR library screening and RNA sequencing.
  • In vitro and in vivo experiments including micrococcal nuclease assay and drug rescue assays.
  • Overexpression, silencing, TurboID-based mass spectrometry, and immunoprecipitation (IP).

Main Results:

  • ATP2B4 was identified as a novel contributor to pancreatic cancer radio-resistance.
  • ATP2B4 knockout led to chromatin decompaction via histone H1.0 downregulation, increasing DNA damage and apoptosis.
  • ATP2B4 stabilizes ELAVL1, regulating histone H1.0 mRNA stability.

Conclusions:

  • ATP2B4 is a key regulator of chromatin compaction and DNA damage response in pancreatic cancer.
  • ATP2B4 inhibition may overcome radio-resistance (RTR).
  • ATP2B4 serves as a potential biomarker for predicting radiotherapy outcomes.

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