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Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant

Meng-Tzu Weng1, Jih-Hsiang Lee, Shu-Chen Wei

  • 1Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 14, 2012
PubMed

Insights

Cancer cells with KRAS mutations depend on the enhancer of rudimentary homolog (ERH) gene for survival. Depleting ERH causes toxicity in these cells, highlighting ERH as a potential therapeutic target for KRAS-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cancers with Ras mutations present significant therapeutic challenges.
  • Ras mutant cells rely on specific nononcogene addiction pathways for survival.
  • Identifying vulnerabilities in Ras-driven cancers is crucial for developing new treatments.

Purpose of the Study:

  • To identify novel genes essential for the survival of cancer cells harboring KRAS mutations.
  • To investigate the functional role of the enhancer of rudimentary homolog (ERH) gene in KRAS-mutant cancers.
  • To explore ERH's mechanism of action and its clinical relevance.

Main Methods:

  • RNA interference (RNAi) screens to identify essential genes in Ras mutant cells.
  • Depletion of ERH in KRAS mutant versus wild-type (WT) cancer cells.
  • Interaction studies with spliceosome components (SNRPD3).
  • Analysis of mRNA splicing and protein expression (CENP-E).
  • Gene expression profiling and correlation with KRAS signatures.
  • Clinical analysis of ERH expression in colorectal cancer patient cohorts.

Main Results:

  • Depletion of ERH exhibited greater toxicity in KRAS-mutant cancer cells compared to KRAS WT cells.
  • ERH interacts with SNRPD3 and is critical for the mRNA splicing of CENP-E.
  • Loss of ERH led to decreased CENP-E levels and subsequent chromosome congression defects.
  • ERH is required for the expression of multiple cell cycle genes, with its downregulation signature inversely correlating with KRAS signatures.
  • Tumor ERH expression inversely correlates with survival in colorectal cancer patients with KRAS mutations.

Conclusions:

  • ERH plays a vital role in mRNA splicing and mitosis, essential for KRAS-mutant cancer cell survival.
  • KRAS-mutant cancer cells exhibit a dependency on ERH, presenting a potential therapeutic vulnerability.
  • ERH represents a promising target for developing novel therapies against KRAS-driven cancers.

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