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Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death
BACKGROUND: Colorectal cancer (CRC) frequently has a dysregulated epigenome causing aberrant up-regulation of oncogenes such as c-MYC. Bromodomain and extra-terminal domain (BET) proteins and histone acetyltransferases (HAT) are epigenetic regulatory proteins that create and maintain epigenetic stat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599411/ https://www.ncbi.nlm.nih.gov/pubmed/36313707 http://dx.doi.org/10.3389/fonc.2022.1018775 |
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author | Kuang, Chaoyuan Tong, Jingshan Ermine, Kaylee Cai, Manbo Dai, Fujun Hao, Suisui Giles, Francis Huang, Yi Yu, Jian Zhang, Lin |
author_facet | Kuang, Chaoyuan Tong, Jingshan Ermine, Kaylee Cai, Manbo Dai, Fujun Hao, Suisui Giles, Francis Huang, Yi Yu, Jian Zhang, Lin |
author_sort | Kuang, Chaoyuan |
collection | PubMed |
description | BACKGROUND: Colorectal cancer (CRC) frequently has a dysregulated epigenome causing aberrant up-regulation of oncogenes such as c-MYC. Bromodomain and extra-terminal domain (BET) proteins and histone acetyltransferases (HAT) are epigenetic regulatory proteins that create and maintain epigenetic states supporting oncogenesis. BET inhibitors and HAT inhibitors are currently being investigated as cancer therapeutics due to their ability to suppress cancer-promoting epigenetic modifiers. Due to the extensive molecular crosstalk between BET proteins and HAT proteins, we hypothesized that dual inhibition of BET and HAT could more potently inhibit CRC cells than inhibition of each individual protein. METHODS: We investigated the activity and mechanisms of a dual BET and HAT inhibitor, NEO2734, in CRC cell lines and mouse xenografts. MTS, flow cytometry, and microscopy were used to assess cell viability. qPCR, Western blotting, and immunofluorescent staining were used to assess mechanisms of action. RESULTS: We found that NEO2734 more potently suppresses CRC cell growth than first generation BET inhibitors, regardless of the status of common CRC driver mutations. We previously showed that BET inhibitors upregulate DR5 to induce extrinsic apoptosis. In the current study, we show that NEO2734 treatment induces CRC cell apoptosis via both the intrinsic and extrinsic apoptosis pathways. NEO2734 increases p53 expression and subsequently increased expression of the p53-upregulated mediator of apoptosis (PUMA), which is a critical mechanism for activating intrinsic apoptosis. We demonstrate that inhibition of either the intrinsic or extrinsic branches of apoptosis partially rescues CRC cells from NEO2734 treatment, while the dual inhibition of both branches of apoptosis more strongly rescues CRC cells from NEO2734 treatment. Finally, we show that NEO2734 monotherapy is able to suppress tumor growth in CRC xenografts by inducing apoptosis. CONCLUSIONS: Our study demonstrates NEO2734 potently suppresses CRC cells in vitro and in vivo by simultaneously upregulating PUMA and DR5 to induce cell death. Further studies of NEO2734 for treating CRC are warranted. |
format | Online Article Text |
id | pubmed-9599411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95994112022-10-27 Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death Kuang, Chaoyuan Tong, Jingshan Ermine, Kaylee Cai, Manbo Dai, Fujun Hao, Suisui Giles, Francis Huang, Yi Yu, Jian Zhang, Lin Front Oncol Oncology BACKGROUND: Colorectal cancer (CRC) frequently has a dysregulated epigenome causing aberrant up-regulation of oncogenes such as c-MYC. Bromodomain and extra-terminal domain (BET) proteins and histone acetyltransferases (HAT) are epigenetic regulatory proteins that create and maintain epigenetic states supporting oncogenesis. BET inhibitors and HAT inhibitors are currently being investigated as cancer therapeutics due to their ability to suppress cancer-promoting epigenetic modifiers. Due to the extensive molecular crosstalk between BET proteins and HAT proteins, we hypothesized that dual inhibition of BET and HAT could more potently inhibit CRC cells than inhibition of each individual protein. METHODS: We investigated the activity and mechanisms of a dual BET and HAT inhibitor, NEO2734, in CRC cell lines and mouse xenografts. MTS, flow cytometry, and microscopy were used to assess cell viability. qPCR, Western blotting, and immunofluorescent staining were used to assess mechanisms of action. RESULTS: We found that NEO2734 more potently suppresses CRC cell growth than first generation BET inhibitors, regardless of the status of common CRC driver mutations. We previously showed that BET inhibitors upregulate DR5 to induce extrinsic apoptosis. In the current study, we show that NEO2734 treatment induces CRC cell apoptosis via both the intrinsic and extrinsic apoptosis pathways. NEO2734 increases p53 expression and subsequently increased expression of the p53-upregulated mediator of apoptosis (PUMA), which is a critical mechanism for activating intrinsic apoptosis. We demonstrate that inhibition of either the intrinsic or extrinsic branches of apoptosis partially rescues CRC cells from NEO2734 treatment, while the dual inhibition of both branches of apoptosis more strongly rescues CRC cells from NEO2734 treatment. Finally, we show that NEO2734 monotherapy is able to suppress tumor growth in CRC xenografts by inducing apoptosis. CONCLUSIONS: Our study demonstrates NEO2734 potently suppresses CRC cells in vitro and in vivo by simultaneously upregulating PUMA and DR5 to induce cell death. Further studies of NEO2734 for treating CRC are warranted. Frontiers Media S.A. 2022-10-12 /pmc/articles/PMC9599411/ /pubmed/36313707 http://dx.doi.org/10.3389/fonc.2022.1018775 Text en Copyright © 2022 Kuang, Tong, Ermine, Cai, Dai, Hao, Giles, Huang, Yu and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Kuang, Chaoyuan Tong, Jingshan Ermine, Kaylee Cai, Manbo Dai, Fujun Hao, Suisui Giles, Francis Huang, Yi Yu, Jian Zhang, Lin Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title | Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title_full | Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title_fullStr | Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title_full_unstemmed | Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title_short | Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death |
title_sort | dual inhibition of bet and hat/p300 suppresses colorectal cancer via dr5- and p53/puma-mediated cell death |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599411/ https://www.ncbi.nlm.nih.gov/pubmed/36313707 http://dx.doi.org/10.3389/fonc.2022.1018775 |
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