Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetyl...
| Hoofdauteurs: | , , , , , , , , , , , , , , , , , , , , |
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| Formaat: | Journal article |
| Taal: | English |
| Gepubliceerd in: |
Cell Press
2019
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| _version_ | 1826268826051805184 |
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| author | Anastas, JN Zee, BM Kalin, JH Kim, M Guo, R Alexandrescu, S Blanco, MA Giera, S Gillespie, SM Das, J Wu, M Nocco, S Bonal, DM Nguyen, Q-D Suva, ML Bernstein, BE Alani, R Golub, TR Cole, PA Filbin, MG Shi, Y |
| author_facet | Anastas, JN Zee, BM Kalin, JH Kim, M Guo, R Alexandrescu, S Blanco, MA Giera, S Gillespie, SM Das, J Wu, M Nocco, S Bonal, DM Nguyen, Q-D Suva, ML Bernstein, BE Alani, R Golub, TR Cole, PA Filbin, MG Shi, Y |
| author_sort | Anastas, JN |
| collection | OXFORD |
| description | H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs. |
| first_indexed | 2024-03-06T21:15:33Z |
| format | Journal article |
| id | oxford-uuid:3fae49db-2d10-4a57-bbd4-c0e4e76733e7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:15:33Z |
| publishDate | 2019 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:3fae49db-2d10-4a57-bbd4-c0e4e76733e72022-03-26T14:33:27ZRe-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPGJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3fae49db-2d10-4a57-bbd4-c0e4e76733e7EnglishSymplectic ElementsCell Press2019Anastas, JNZee, BMKalin, JHKim, MGuo, RAlexandrescu, SBlanco, MAGiera, SGillespie, SMDas, JWu, MNocco, SBonal, DMNguyen, Q-DSuva, MLBernstein, BEAlani, RGolub, TRCole, PAFilbin, MGShi, YH3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs. |
| spellingShingle | Anastas, JN Zee, BM Kalin, JH Kim, M Guo, R Alexandrescu, S Blanco, MA Giera, S Gillespie, SM Das, J Wu, M Nocco, S Bonal, DM Nguyen, Q-D Suva, ML Bernstein, BE Alani, R Golub, TR Cole, PA Filbin, MG Shi, Y Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title | Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title_full | Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title_fullStr | Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title_full_unstemmed | Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title_short | Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
| title_sort | re programing chromatin with a bifunctional lsd1 hdac inhibitor induces therapeutic differentiation in dipg |
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