Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

Yang Bian, Risa Kitagawa, Parmil K. Bansal, Yo Fujii, Alexander Stepanov, Katsumi Kitagawa

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specifically make cancer cells susceptible to death by inducing a synthetic dosage lethality defect. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a synthetic genetic array analysis in yeast, which revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of candidate genes, knockdown of PPP2R1A, a gene encoding a constant regulatory subunit of protein phosphatase 2, significantly inhibited the growth of Mad2-overexpressing tumor cells. PPP2R1A inhibition induced Mad2 phosphorylation and suppressed Mad2 protein levels. Depletion of PPP2R1A inhibited colony formation of Mad2-overexpressing HeLa cells but not of unphosphorylated Mad2 mutant-overexpressing cells, suggesting that the lethality induced by PP2A depletion in Mad2- overexpressing cells is dependent on Mad2 phosphorylation. Also, the PP2A inhibitor cantharidin induced Mad2 phosphorylation and inhibited the growth of Mad2-overexpressing cancer cells. Aurora B knockdown inhibited Mad2 phosphorylation in mitosis, resulting in the blocking of PPP2R1A inhibition-induced cell death. Taken together, our results strongly suggest that PP2A is a good therapeutic target in Mad2-overexpressing tumors.

Original languageEnglish (US)
Pages (from-to)1628-1633
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number4
DOIs
StatePublished - Jan 28 2014
Externally publishedYes

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Keywords

  • Aneuploidy
  • Anticancer drug
  • Cancer therapy target
  • Yeast genetics

ASJC Scopus subject areas

  • General

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