Identification of a novel metastasis inducing lncRNA which suppresses the KAI1/CD82 metastasis suppressor gene and is upregulated in triple-negative breast cancer
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Ronni Aram1, Iris Dotan1, Agnes Hotz-Wagenblatt2 and Dan Canaani1
1Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel
2Bioinformatics Group, Core Facility Genomics & Proteomics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
Dan Canaani, email: [email protected]
Keywords: lncRNA, metastasis suppressor genes, triple-negative breast cancer, epigenetic gene regulation, lncRNA and metastasis
Received: April 13, 2017 Accepted: May 23, 2017 Published: June 28, 2017
Inactivation of tumor/metastasis suppressor genes via epigenetic silencing is a frequent event in human cancers. KAI1/CD82 is a metastasis suppressor gene whose normal protecting activity is deficient in twelve different solid malignancies. Here we have identified and characterized a primarily nuclear non-polyadenylated, antisense (as)-lncRNA, initiating upstream of the KAI1 human metastasis suppressor gene transcription start site; and elongating in the opposite direction to KAI1 mRNA. We show that the KAI1 promoter is bi-directional giving rise to KAI1 mRNA and its as-lncRNA. Moreover, expression of this lncRNA transcript emerges to be inversely related to the KAI1 mRNA expression, and in direct relationship to the invasiveness level of human breast cancer derived cell lines. Importantly, knockdown of the KAI1 as-lncRNA in the triple-negative breast cancer cell line MDA-MB-231 have led to increased KAI1 mRNA and protein expression, manifested in stronger adhesion to fibronectin, retardation of cell migration and reduced cell invasion in vitro. Accordingly we have named this lncRNA, SKAI1BC, standing for “Suppressor of KAI1 in Breast Cancer”. These results uncover a potential way to harness tumor metastasis via targeting SKAI1BC in human breast cancer, and perhaps also in other KAI1-deficient human malignancies.
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