ADAR1-mediated regulation of melanoma invasion

• Published in: Nature communications Vol. 9; no. 1; pp. 2154 - 13
• Main Authors: Nemlich, Yael, Baruch, Erez Nissim, Besser, Michal Judith, Shoshan, Einav, Bar-Eli, Menashe, Anafi, Liat, Barshack, Iris, Schachter, Jacob, Ortenberg, Rona, Markel, Gal
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 31.05.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: 3' Untranslated Regions - genetics; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Antibodies; Cancer; Cell Line, Tumor; Cell migration; Control; DNA microarrays; Editing; Gene expression; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Immunohistochemistry; Integrin beta3 - genetics; Integrin beta3 - metabolism; Invasiveness; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastases; MicroRNAs - genetics; Neoplasm Invasiveness; Neoplasm Metastasis; Pax6 protein; Post-transcription; Regulators; Ribonucleic acid; RNA; RNA Editing; RNA Interference; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04600-2

Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.