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GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling

Khanna, Puja, Lee, Joan Shuying, Sereemaspun, Amornpun, Lee, Haeryun, Baeg, Gyeong Hun·2018·Scientific Reports
DOI 10.1038/s41598-018-27864-6PMC PMC6015000
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Abstract

Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.

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Metadata

Authors
Khanna, P., Lee, J. S., Sereemaspun, A., Lee, H., & Baeg, G. H.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-06-22
Volume
8
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-018-27864-6
PMC
PMC6015000
Cited by
48
References
2
Language
en
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