The polyamine catabolic enzyme sat1 modulates tumorigenesis and radiation response in gbm

Adina Brett-Morris, Bradley M. Wright, Yuji Seo, Vinay Pasupuleti, Junran Zhang, Jun Lu, Raffaella Spina, Eli E. Bar, Maneesh Gujrati, Rebecca Schur, Zheng Rong Lu, Scott M. Welford

Research output: Contribution to journalArticle

Abstract

Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. To understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes in which inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2-Mand S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biologic signi ficance of elevated SAT1 expression inGBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitizeGBMto cancer therapies.

Original languageEnglish (US)
Pages (from-to)6925-6934
Number of pages10
JournalCancer Research
Volume74
Issue number23
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Brett-Morris, A., Wright, B. M., Seo, Y., Pasupuleti, V., Zhang, J., Lu, J., Spina, R., Bar, E. E., Gujrati, M., Schur, R., Lu, Z. R., & Welford, S. M. (2014). The polyamine catabolic enzyme sat1 modulates tumorigenesis and radiation response in gbm. Cancer Research, 74(23), 6925-6934. https://doi.org/10.1158/0008-5472.CAN-14-1249