Open AccessLoss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling
Author(s) -
Shamik Das,
W. P. U. Jackson,
Jeevan K. Prasain,
Ann Hanna,
Sarah Bailey,
J. Allan Tucker,
Sejong Bae,
Landon Wilson,
Rajeev S. Samant,
Stephen Barnes,
Lalita A. Shevde
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep40773
Subject(s) - merlin (protein) , hedgehog , hedgehog signaling pathway , biology , gli1 , metabolomics , cancer research , phenotype , signal transduction , metabolome , microbiology and biotechnology , cancer , suppressor , bioinformatics , genetics , gene
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.