Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma
Abstract PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This stu...
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doaj-5efec489251247878b469f04eabfdbe72021-04-11T11:05:20ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411510.1038/s41419-021-03657-0Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastomaSeung Won Choi0Yeri Lee1Kayoung Shin2Harim Koo3Donggeon Kim4Jason K. Sa5Hee Jin Cho6Hye-mi Shin7Se Jeong Lee8Hyunho Kim9Seok Chung10Jihye Shin11Cheolju Lee12Do-Hyun Nam13Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical CenterInstitute for Refractory Cancer Research, Samsung Medical CenterDepartment of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan UniversityDepartment of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan UniversityInstitute for Refractory Cancer Research, Samsung Medical CenterBK21 Graduate Program, Department of Biomedical Sciences, Korea University College of MedicineResearch Institute for Future Medicine, Samsung Medical CenterResearch Institute for Future Medicine, Samsung Medical CenterDepartment of Anatomy, Korea University College of MedicineSchool of Mechanical Engineering, College of Engineering, Korea UniversitySchool of Mechanical Engineering, College of Engineering, Korea UniversityCenter for Theragnosis, Korea Institute of Science and TechnologyCenter for Theragnosis, Korea Institute of Science and TechnologyDepartment of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical CenterAbstract PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.https://doi.org/10.1038/s41419-021-03657-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seung Won Choi Yeri Lee Kayoung Shin Harim Koo Donggeon Kim Jason K. Sa Hee Jin Cho Hye-mi Shin Se Jeong Lee Hyunho Kim Seok Chung Jihye Shin Cheolju Lee Do-Hyun Nam |
spellingShingle |
Seung Won Choi Yeri Lee Kayoung Shin Harim Koo Donggeon Kim Jason K. Sa Hee Jin Cho Hye-mi Shin Se Jeong Lee Hyunho Kim Seok Chung Jihye Shin Cheolju Lee Do-Hyun Nam Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma Cell Death and Disease |
author_facet |
Seung Won Choi Yeri Lee Kayoung Shin Harim Koo Donggeon Kim Jason K. Sa Hee Jin Cho Hye-mi Shin Se Jeong Lee Hyunho Kim Seok Chung Jihye Shin Cheolju Lee Do-Hyun Nam |
author_sort |
Seung Won Choi |
title |
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma |
title_short |
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma |
title_full |
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma |
title_fullStr |
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma |
title_full_unstemmed |
Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma |
title_sort |
mutation-specific non-canonical pathway of pten as a distinct therapeutic target for glioblastoma |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-04-01 |
description |
Abstract PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target. |
url |
https://doi.org/10.1038/s41419-021-03657-0 |
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