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Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness
MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266391/ https://www.ncbi.nlm.nih.gov/pubmed/34236315 http://dx.doi.org/10.7554/eLife.64212 |
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author | Mathsyaraja, Haritha Catchpole, Jonathen Freie, Brian Eastwood, Emily Babaeva, Ekaterina Geuenich, Michael Cheng, Pei Feng Ayers, Jessica Yu, Ming Wu, Nan Moorthi, Sitapriya Poudel, Kumud R Koehne, Amanda Grady, William Houghton, A McGarry Berger, Alice H Shiio, Yuzuru MacPherson, David Eisenman, Robert N |
author_facet | Mathsyaraja, Haritha Catchpole, Jonathen Freie, Brian Eastwood, Emily Babaeva, Ekaterina Geuenich, Michael Cheng, Pei Feng Ayers, Jessica Yu, Ming Wu, Nan Moorthi, Sitapriya Poudel, Kumud R Koehne, Amanda Grady, William Houghton, A McGarry Berger, Alice H Shiio, Yuzuru MacPherson, David Eisenman, Robert N |
author_sort | Mathsyaraja, Haritha |
collection | PubMed |
description | MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex. |
format | Online Article Text |
id | pubmed-8266391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-82663912021-07-12 Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness Mathsyaraja, Haritha Catchpole, Jonathen Freie, Brian Eastwood, Emily Babaeva, Ekaterina Geuenich, Michael Cheng, Pei Feng Ayers, Jessica Yu, Ming Wu, Nan Moorthi, Sitapriya Poudel, Kumud R Koehne, Amanda Grady, William Houghton, A McGarry Berger, Alice H Shiio, Yuzuru MacPherson, David Eisenman, Robert N eLife Cancer Biology MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex. eLife Sciences Publications, Ltd 2021-07-08 /pmc/articles/PMC8266391/ /pubmed/34236315 http://dx.doi.org/10.7554/eLife.64212 Text en © 2021, Mathsyaraja et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Mathsyaraja, Haritha Catchpole, Jonathen Freie, Brian Eastwood, Emily Babaeva, Ekaterina Geuenich, Michael Cheng, Pei Feng Ayers, Jessica Yu, Ming Wu, Nan Moorthi, Sitapriya Poudel, Kumud R Koehne, Amanda Grady, William Houghton, A McGarry Berger, Alice H Shiio, Yuzuru MacPherson, David Eisenman, Robert N Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title | Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title_full | Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title_fullStr | Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title_full_unstemmed | Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title_short | Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
title_sort | loss of mga repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266391/ https://www.ncbi.nlm.nih.gov/pubmed/34236315 http://dx.doi.org/10.7554/eLife.64212 |
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