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A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1α-XBP1 Activation

Zhifen Yang1, Jing Zhang1, Dadi Jiang2

  • 1Department of Radiation Oncology, Stanford University, Stanford, California.

Molecular Cancer Research : MCR
|February 15, 2018
PubMed

Insights

A genome-wide screen identified 162 genes regulating the unfolded protein response (UPR) via the IRE1α-XBP1 pathway. Some genes, like GCLM, are linked to worse survival in breast cancer patients, suggesting new therapeutic targets for UPR modulation.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signaling Pathways

Background:

  • The unfolded protein response (UPR) is implicated in human diseases, notably cancer.
  • The inositol-requiring kinase 1α (IRE1α)-X-box binding protein 1 (XBP1) pathway is a critical UPR signaling branch.
  • Understanding genes that modulate the IRE1α-XBP1 axis is crucial for cancer research.

Purpose of the Study:

  • To systematically identify genes involved in the IRE1α-XBP1 signaling pathway using a genome-wide screen.
  • To explore the role of these identified genes in cancer pathogenesis, particularly breast cancer.
  • To uncover novel therapeutic strategies targeting the UPR in cancer.

Main Methods:

  • Conducted a genome-wide siRNA screen in cells expressing an XBP1-luciferase reporter.
  • Monitored alterations in XBP1 splicing upon gene inhibition.
  • Performed pathway analysis and correlated gene expression with patient survival data.

Main Results:

  • Identified 162 genes that modulate XBP1 splicing when inhibited by siRNA.
  • These genes regulate diverse cellular processes and include those implicated in breast cancer.
  • High GCLM expression correlated with worse relapse-free survival in both triple-negative and non-triple-negative breast cancer patients.

Conclusions:

  • The study reveals novel genes and pathways regulating the IRE1α-XBP1 signaling pathway.
  • Findings provide a foundation for developing new therapeutic approaches targeting the UPR in cancer.
  • Modulating the UPR presents a promising paradigm for cancer treatment.

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