MX2 mediates establishment of interferon response profile, regulates XAF1, and can sensitize melanoma cells to targeted therapy

MX2 is an interferon inducible gene that is mostly known for its antiviral activity. We have previously demonstrated that MX2 is also associated with the tumorigenesis process in melanoma. However, it remains unknown which molecular mechanisms are regulated by MX2 in response to interferon signaling...

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Bibliographic Details
Published in:Cancer medicine (Malden, MA) MA), 2021-04, Vol.10 (8), p.2840-2854
Main Authors: Juraleviciute, Marina, Nsengimana, Jérémie, Newton‐Bishop, Julia, Hendriks, Gert J., Slipicevic, Ana
Format: Article
Language:English
Subjects:
Antiviral activity
Antiviral agents
Apoptosis
Cancer Biology
Cell cycle
Cell growth
Experiments
Gene expression
Interferon
Kinases
Melanoma
melanoma‐specific survival
Metastases
Molecular modelling
MX2
Original Research
Phosphorylation
Proteins
Reagents
Skin cancer
STAT1 phosphorylation
Stat1 protein
Transcription
Tumor suppressor genes
Tumorigenesis
Tumors
XAF1
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Summary:MX2 is an interferon inducible gene that is mostly known for its antiviral activity. We have previously demonstrated that MX2 is also associated with the tumorigenesis process in melanoma. However, it remains unknown which molecular mechanisms are regulated by MX2 in response to interferon signaling in this disease. Here, we report that MX2 is necessary for the establishment of an interferon‐induced transcriptional profile partially through regulation of STAT1 phosphorylation and other interferon‐related downstream factors, including proapoptotic tumor suppressor XAF1. MX2 and XAF1 expression tightly correlate in both cultured melanoma cell lines and in patient‐derived primary and metastatic tumors, where they also are significantly related with survival. MX2 mediates IFN growth‐inhibitory signals in both XAF1 dependent and independent ways and in a cell type and context‐dependent manner. Higher MX2 expression renders melanoma cells more sensitive to targeted therapy drugs such as vemurafenib and trametinib; however, this effect is XAF1 independent. In summary, we uncovered a new mechanism in the complex regulation of interferon signaling in melanoma that can influence both survival and response to therapy. MX2 upregulation establishes an interferon‐induced transcriptional profile in melanoma cells. MX2 regulates tumor suppressor XAF1 and sensitizes melanoma cells to targeted therapy drugs such as vemurafenib and trametinib.
ISSN:2045-7634
2045-7634
DOI:10.1002/cam4.3846