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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
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.
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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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