Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors
Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Springer Nature
2017
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| _version_ | 1797054543711698944 |
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| author | Lines, K Stevenson, M Filippakopoulos, P Müller, S Lockstone, H Wright, B Grozinsky-Glasberg, S Grossman, A Knapp, S Buck, D Bountra, C Thakker, R |
| author_facet | Lines, K Stevenson, M Filippakopoulos, P Müller, S Lockstone, H Wright, B Grozinsky-Glasberg, S Grossman, A Knapp, S Buck, D Bountra, C Thakker, R |
| author_sort | Lines, K |
| collection | OXFORD |
| description | Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and extra terminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by propidium iodide staining and flow cytometry, resulting in increased and decreased proportions of NET cells in G1, and S and G2 phases, respectively. RNA Sequencing analysis revealed that these JQ1 effects were associated with increased histone 2B expression, and likely mediated through altered activity of bromodomain-containing (Brd) proteins. Assessment of JQ1 in vivo, using a pancreatic beta cell-specific conditional Men1 knockout mouse model that develops PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, P<0.0005), assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, P<0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors may provide new treatments for NETs. |
| first_indexed | 2024-03-06T18:58:41Z |
| format | Journal article |
| id | oxford-uuid:12c588c4-25ef-48d7-9e37-ab06b829f773 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:58:41Z |
| publishDate | 2017 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:12c588c4-25ef-48d7-9e37-ab06b829f7732022-03-26T10:09:49ZEpigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:12c588c4-25ef-48d7-9e37-ab06b829f773EnglishSymplectic Elements at OxfordSpringer Nature2017Lines, KStevenson, MFilippakopoulos, PMüller, SLockstone, HWright, BGrozinsky-Glasberg, SGrossman, AKnapp, SBuck, DBountra, CThakker, RCancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and extra terminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by propidium iodide staining and flow cytometry, resulting in increased and decreased proportions of NET cells in G1, and S and G2 phases, respectively. RNA Sequencing analysis revealed that these JQ1 effects were associated with increased histone 2B expression, and likely mediated through altered activity of bromodomain-containing (Brd) proteins. Assessment of JQ1 in vivo, using a pancreatic beta cell-specific conditional Men1 knockout mouse model that develops PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, P<0.0005), assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, P<0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors may provide new treatments for NETs. |
| spellingShingle | Lines, K Stevenson, M Filippakopoulos, P Müller, S Lockstone, H Wright, B Grozinsky-Glasberg, S Grossman, A Knapp, S Buck, D Bountra, C Thakker, R Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title | Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title_full | Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title_fullStr | Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title_full_unstemmed | Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title_short | Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
| title_sort | epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors |
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