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Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling

The tumor suppressor protein Merlin is proteasomally degraded in breast cancer. We undertook an untargeted metabolomics approach to discern the global metabolomics profile impacted by Merlin in breast cancer cells. We discerned specific changes in glutathione metabolites that uncovered novel facets...

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Autores principales: Das, Shamik, Jackson, William P., Prasain, Jeevan K., Hanna, Ann, Bailey, Sarah K., Tucker, J. Allan, Bae, Sejong, Wilson, Landon S., Samant, Rajeev S., Barnes, Stephen, Shevde, Lalita A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256100/
https://www.ncbi.nlm.nih.gov/pubmed/28112165
http://dx.doi.org/10.1038/srep40773
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author Das, Shamik
Jackson, William P.
Prasain, Jeevan K.
Hanna, Ann
Bailey, Sarah K.
Tucker, J. Allan
Bae, Sejong
Wilson, Landon S.
Samant, Rajeev S.
Barnes, Stephen
Shevde, Lalita A.
author_facet Das, Shamik
Jackson, William P.
Prasain, Jeevan K.
Hanna, Ann
Bailey, Sarah K.
Tucker, J. Allan
Bae, Sejong
Wilson, Landon S.
Samant, Rajeev S.
Barnes, Stephen
Shevde, Lalita A.
author_sort Das, Shamik
collection PubMed
description The tumor suppressor protein Merlin is proteasomally degraded in breast cancer. We undertook an untargeted metabolomics approach to discern the global metabolomics profile impacted by Merlin in breast cancer cells. We discerned specific changes in glutathione metabolites that uncovered novel facets of Merlin in impacting the cancer cell metabolome. Concordantly, Merlin loss increased oxidative stress causing aberrant activation of Hedgehog signaling. Abrogation of GLI-mediated transcription activity compromised the aggressive phenotype of Merlin-deficient cells indicating a clear dependence of cells on Hedgehog signaling. In breast tumor tissues, GLI1 expression enhanced tissue identification and discriminatory power of Merlin, cumulatively presenting a powerful substantiation of the relationship between these two proteins. We have uncovered, for the first time, details of the tumor cell metabolomic portrait modulated by Merlin, leading to activation of Hedgehog signaling. Importantly, inhibition of Hedgehog signaling offers an avenue to target the vulnerability of tumor cells with loss of Merlin.
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spelling pubmed-52561002017-01-24 Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling Das, Shamik Jackson, William P. Prasain, Jeevan K. Hanna, Ann Bailey, Sarah K. Tucker, J. Allan Bae, Sejong Wilson, Landon S. Samant, Rajeev S. Barnes, Stephen Shevde, Lalita A. Sci Rep Article The tumor suppressor protein Merlin is proteasomally degraded in breast cancer. We undertook an untargeted metabolomics approach to discern the global metabolomics profile impacted by Merlin in breast cancer cells. We discerned specific changes in glutathione metabolites that uncovered novel facets of Merlin in impacting the cancer cell metabolome. Concordantly, Merlin loss increased oxidative stress causing aberrant activation of Hedgehog signaling. Abrogation of GLI-mediated transcription activity compromised the aggressive phenotype of Merlin-deficient cells indicating a clear dependence of cells on Hedgehog signaling. In breast tumor tissues, GLI1 expression enhanced tissue identification and discriminatory power of Merlin, cumulatively presenting a powerful substantiation of the relationship between these two proteins. We have uncovered, for the first time, details of the tumor cell metabolomic portrait modulated by Merlin, leading to activation of Hedgehog signaling. Importantly, inhibition of Hedgehog signaling offers an avenue to target the vulnerability of tumor cells with loss of Merlin. Nature Publishing Group 2017-01-23 /pmc/articles/PMC5256100/ /pubmed/28112165 http://dx.doi.org/10.1038/srep40773 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Das, Shamik
Jackson, William P.
Prasain, Jeevan K.
Hanna, Ann
Bailey, Sarah K.
Tucker, J. Allan
Bae, Sejong
Wilson, Landon S.
Samant, Rajeev S.
Barnes, Stephen
Shevde, Lalita A.
Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title_full Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title_fullStr Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title_full_unstemmed Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title_short Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
title_sort loss of merlin induces metabolomic adaptation that engages dependence on hedgehog signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256100/
https://www.ncbi.nlm.nih.gov/pubmed/28112165
http://dx.doi.org/10.1038/srep40773
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