Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma

Fengting Yan, Lapo Alinari, Mark E. Lustberg, Ludmila Katherine Martin, Hector M. Cordero-Nieves, Yeshavanth Banasavadi-Siddegowda, Selene Virk, Jill Barnholtz-Sloan, Erica Hlavin Bell, Jeffrey Wojton, Naduparambil K. Jacob, Arnab Chakravarti, Michal O. Nowicki, Xin Wu, Rosa Lapalombella, Jharna Datta, Bo Yu, Kate Gordon, Amy Haseley, John T. PattonPorsha L. Smith, John Ryu, Xiaoli Zhang, Xiaokui Mo, Guido Marcucci, Gerard Nuovo, Chang Hyuk Kwon, John C. Byrd, E. Antonio Chiocca, Chenglong Li, Said Sif, Samson Jacob, Sean Lawler, Balveen Kaur, Robert A. Baiocchi

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.

Original languageEnglish (US)
Pages (from-to)1752-1765
Number of pages14
JournalCancer Research
Issue number6
StatePublished - Mar 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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