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Updated: Jun 5, 2026

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

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YARS2 mediates PARPi resistance in pancreatic cancer by regulating the MYC-E2F axis

Yu Hu1, Peng Yuan1, Xiangyi Bu1

  • 1Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Acta Histochemica
|June 3, 2026
PubMed
Abstract

Insights

Yeast RNA Splicing 2 (YARS2) drives resistance to PARP inhibitors (PARPi) in pancreatic cancer by activating the MYC/E2F1 pathway. Targeting YARS2 may overcome PARPi resistance in pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to PARP inhibitors (PARPi).
  • The underlying mechanisms of PARPi resistance in PDAC are not fully understood.

Purpose of the Study:

  • To identify key genes associated with PARPi resistance in PDAC.
  • To elucidate the molecular mechanisms by which YARS2 influences PARPi resistance.

Main Methods:

  • Integrated multi-omics data analysis (TCGA-PAAD, CCLE, GDSC) and Weighted Gene Co-expression Network Analysis (WGCNA).
  • Differential gene expression analysis, functional enrichment, and in vitro/in vivo experiments including cell assays and xenograft models.
  • Quantitative reverse transcription PCR (qRT-PCR) and western blotting (WB) for gene and protein expression analysis.

Main Results:

  • Yeast RNA Splicing 2 (YARS2) was identified as a crucial hub gene promoting PARPi resistance in PDAC.
  • High YARS2 expression correlated with poor prognosis; its knockdown sensitized PDAC cells to PARPi in vitro and in vivo.
  • YARS2 knockdown suppressed MYC/E2F1 expression and increased γ-H2AX levels, with MYC overexpression reversing YARS2 knockdown's effect.

Conclusions:

  • YARS2 mediates PARPi resistance in PDAC through the MYC/E2F1 pathway.
  • YARS2 represents a potential therapeutic target for overcoming PARPi resistance in pancreatic cancer.
Keywords:
Drug resistance mechanismMYC/E2F1 pathwayMitochondrial functionPARP inhibitorsYARS2

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