Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma.
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.
Authors' Affiliations: Division of Hematology, Department of Internal Medicine; Division of Infectious Diseases, Department of Internal Medicine; Departments of Neurosurgery; Molecular and Cellular Biochemistry; Chemical Engineering; Statistics; Pathology; Radiation Oncology; and College of Pharmacy, The Ohio State University (OSU), Columbus; Case Comprehensive Cancer Center; and Department of Epidemiology and Biostatistics, CWRU School of Medicine, Cleveland, Ohio.
Fengting
F
Yan
Lapo
L
Alinari
Mark E
ME
Lustberg
Ludmila Katherine
LK
Martin
Hector M
HM
Cordero-Nieves
Yeshavanth
Y
Banasavadi-Siddegowda
Selene
S
Virk
Jill
J
Barnholtz-Sloan
Erica Hlavin
EH
Bell
Jeffrey
J
Wojton
Naduparambil K
NK
Jacob
Arnab
A
Chakravarti
Michal O
MO
Nowicki
Xin
X
Wu
Rosa
R
Lapalombella
Jharna
J
Datta
Bo
B
Yu
Kate
K
Gordon
Amy
A
Haseley
John T
JT
Patton
Porsha L
PL
Smith
John
J
Ryu
Xiaoli
X
Zhang
Xiaokui
X
Mo
Guido
G
Marcucci
Gerard
G
Nuovo
Chang-Hyuk
CH
Kwon
John C
JC
Byrd
E Antonio
EA
Chiocca
Chenglong
C
Li
Said
S
Sif
Samson
S
Jacob
Sean
S
Lawler
Balveen
B
Kaur
Robert A
RA
Baiocchi
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology* / Q000401:mortality / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D034741:RNA, Small Interfering; C412123:ST7 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases