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PRMT5–PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells
Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to...
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Published in: | Oncogene 2017-01, Vol.36 (2), p.263-274 |
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container_title | Oncogene |
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description | Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumour growth in mice. Here, we report the critical role of PRMT5 in GBM differentiated cells (GBMDC) grown in serum and GBM neurospheres (GBMNS) grown as neurospheres
in vitro
. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS.
In vivo
transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations. |
doi_str_mv | 10.1038/onc.2016.199 |
format | article |
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in vitro
. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS.
In vivo
transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2016.199</identifier><identifier>PMID: 27292259</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/109 ; 13/2 ; 13/31 ; 13/89 ; 38/79 ; 42/100 ; 631/67/1922 ; 631/67/71 ; 64/60 ; Animals ; Apoptosis ; Brain ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Care and treatment ; Cell Biology ; Cell Cycle ; Cell Self Renewal ; Cellular Senescence ; Cellular signal transduction ; Development and progression ; Gene expression ; Genetic aspects ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Glioblastomas ; Health aspects ; Human Genetics ; Humans ; Innovations ; Internal Medicine ; Medicine ; Medicine & Public Health ; Mice ; Molecular targeted therapy ; Neoplasm Transplantation ; Oncogenes ; Oncology ; original-article ; Protein expression ; Protein-Arginine N-Methyltransferases - metabolism ; PTEN Phosphohydrolase - metabolism ; Senescence ; Signal Transduction ; Spheroids, Cellular - cytology ; Spheroids, Cellular - metabolism ; Tumor Cells, Cultured - cytology ; Tumor Cells, Cultured - metabolism ; Tumors</subject><ispartof>Oncogene, 2017-01, Vol.36 (2), p.263-274</ispartof><rights>Macmillan Publishers Limited 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 12, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c550t-7e1c82831aa0d20ee8cf2ae48b4b3b92396ef6a1930075bf41347e0b98bebd943</citedby><cites>FETCH-LOGICAL-c550t-7e1c82831aa0d20ee8cf2ae48b4b3b92396ef6a1930075bf41347e0b98bebd943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27292259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banasavadi-Siddegowda, Y K</creatorcontrib><creatorcontrib>Russell, L</creatorcontrib><creatorcontrib>Frair, E</creatorcontrib><creatorcontrib>Karkhanis, V A</creatorcontrib><creatorcontrib>Relation, T</creatorcontrib><creatorcontrib>Yoo, J Y</creatorcontrib><creatorcontrib>Zhang, J</creatorcontrib><creatorcontrib>Sif, S</creatorcontrib><creatorcontrib>Imitola, J</creatorcontrib><creatorcontrib>Baiocchi, R</creatorcontrib><creatorcontrib>Kaur, B</creatorcontrib><title>PRMT5–PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumour growth in mice. Here, we report the critical role of PRMT5 in GBM differentiated cells (GBMDC) grown in serum and GBM neurospheres (GBMNS) grown as neurospheres
in vitro
. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS.
In vivo
transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations.</description><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/89</subject><subject>38/79</subject><subject>42/100</subject><subject>631/67/1922</subject><subject>631/67/71</subject><subject>64/60</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Brain</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell Cycle</subject><subject>Cell Self Renewal</subject><subject>Cellular Senescence</subject><subject>Cellular signal transduction</subject><subject>Development and progression</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Banasavadi-Siddegowda, Y K</au><au>Russell, L</au><au>Frair, E</au><au>Karkhanis, V A</au><au>Relation, T</au><au>Yoo, J Y</au><au>Zhang, J</au><au>Sif, S</au><au>Imitola, J</au><au>Baiocchi, R</au><au>Kaur, B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PRMT5–PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2017-01-12</date><risdate>2017</risdate><volume>36</volume><issue>2</issue><spage>263</spage><epage>274</epage><pages>263-274</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Glioblastoma (GBM) represents the most common and aggressive histologic subtype among malignant astrocytoma and is associated with poor outcomes because of heterogeneous tumour cell population including mature non-stem-like cell and immature stem-like cells within the tumour. Thus, it is critical to find new target-specific therapeutic modalities. Protein arginine methyltransferase enzyme 5 (PRMT5) regulates many cellular processes through its methylation activity and its overexpression in GBM is associated with more aggressive disease. Previously, we have shown that silencing of PRMT5 expression in differentiated GBM cell lines results in apoptosis and reduced tumour growth in mice. Here, we report the critical role of PRMT5 in GBM differentiated cells (GBMDC) grown in serum and GBM neurospheres (GBMNS) grown as neurospheres
in vitro
. Our results uncover a very significant role for PRMT5 in GBMNS self-renewal capacity and proliferation. PRMT5 knockdown in GBMDC led to apoptosis, knockdown in GBMNS led to G1 cell cycle arrest through upregulation of p27 and hypophoshorylation of retinoblastoma protein, leading to senescence. Comparison of impact of PRMT5 on cellular signalling by the Human Phospho-Kinase Array and chromatin immunoprecipitation-PCR revealed that unlike GBMDC, PRMT5 regulates PTEN expression and controls Akt and ERk activity in GBMNS.
In vivo
transient depletion of PRMT5 decreased intracranial tumour size and growth rate in mice implanted with both primary tumour-derived GBMNS and GBMDC. This is the first study to identify PTEN as a potential downstream target of PRMT5 and PRMT5 is vital to support both mature and immature GBM tumour cell populations.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27292259</pmid><doi>10.1038/onc.2016.199</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 13/1 13/106 13/109 13/2 13/31 13/89 38/79 42/100 631/67/1922 631/67/71 64/60 Animals Apoptosis Brain Brain Neoplasms - metabolism Brain Neoplasms - pathology Care and treatment Cell Biology Cell Cycle Cell Self Renewal Cellular Senescence Cellular signal transduction Development and progression Gene expression Genetic aspects Glioblastoma - metabolism Glioblastoma - pathology Glioblastomas Health aspects Human Genetics Humans Innovations Internal Medicine Medicine Medicine & Public Health Mice Molecular targeted therapy Neoplasm Transplantation Oncogenes Oncology original-article Protein expression Protein-Arginine N-Methyltransferases - metabolism PTEN Phosphohydrolase - metabolism Senescence Signal Transduction Spheroids, Cellular - cytology Spheroids, Cellular - metabolism Tumor Cells, Cultured - cytology Tumor Cells, Cultured - metabolism Tumors |
title | PRMT5–PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells |
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