TY - JOUR
T1 - Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma
AU - Yan, Fengting
AU - Alinari, Lapo
AU - Lustberg, Mark E.
AU - Martin, Ludmila Katherine
AU - Cordero-Nieves, Hector M.
AU - Banasavadi-Siddegowda, Yeshavanth
AU - Virk, Selene
AU - Barnholtz-Sloan, Jill
AU - Bell, Erica Hlavin
AU - Wojton, Jeffrey
AU - Jacob, Naduparambil K.
AU - Chakravarti, Arnab
AU - Nowicki, Michal O.
AU - Wu, Xin
AU - Lapalombella, Rosa
AU - Datta, Jharna
AU - Yu, Bo
AU - Gordon, Kate
AU - Haseley, Amy
AU - Patton, John T.
AU - Smith, Porsha L.
AU - Ryu, John
AU - Zhang, Xiaoli
AU - Mo, Xiaokui
AU - Marcucci, Guido
AU - Nuovo, Gerard
AU - Kwon, Chang Hyuk
AU - Byrd, John C.
AU - Chiocca, E. Antonio
AU - Li, Chenglong
AU - Sif, Said
AU - Jacob, Samson
AU - Lawler, Sean
AU - Kaur, Balveen
AU - Baiocchi, Robert A.
PY - 2014/3/15
Y1 - 2014/3/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84896515012&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-0884
DO - 10.1158/0008-5472.CAN-13-0884
M3 - Article
C2 - 24453002
AN - SCOPUS:84896515012
SN - 0008-5472
VL - 74
SP - 1752
EP - 1765
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -