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USP39 Deubiquitinase Is Essential for KRAS Oncogene-driven Cancer

Julia M Fraile1,2, Eusebio Manchado3, Amaia Lujambio3

  • 1From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.

The Journal of Biological Chemistry
|February 4, 2017
PubMed

Insights

Targeting KRAS-mutant cancers is difficult. Researchers found USP39, a splicing factor, is essential for KRAS-dependent cells, suggesting splicing-directed therapies for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations are common in human cancers, posing therapeutic challenges.
  • USP39 is identified as a crucial splicing factor in KRAS-dependent cells.

Purpose of the Study:

  • To identify novel therapeutic targets for KRAS-mutant cancers.
  • To investigate the role of USP39 in the viability of KRAS-dependent cancer cells.

Main Methods:

  • Synthetic lethal screen using a deubiquitinase library.
  • Depletion of USP39 and DHX38.
  • RNA-sequencing to assess pre-mRNA splicing efficiency.
  • Analysis of USP39 expression in lung and colon carcinomas.

Main Results:

  • USP39 is essential for the viability of KRAS-dependent cancer cells.
  • Splicing fidelity inhibitors preferentially decrease proliferation of KRAS-active cells.
  • USP39 depletion significantly reduces pre-mRNA splicing efficiency.
  • USP39 is upregulated in lung and colon cancers, correlating with KRAS levels and poor prognosis.

Conclusions:

  • USP39 is a critical vulnerability in KRAS-mutant cancers.
  • Targeting USP39 and splicing pathways offers a promising therapeutic strategy for KRAS-driven tumors.
  • USP39 expression levels can serve as a prognostic marker in lung and colon carcinomas.
Keywords:
RNA splicingdegradomedeubiquitylation (deubiquitination)non-oncogene addictionproteaseshort hairpin RNA (shRNA)spliceosomesynthetic lethality

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