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Human Endogenous Retrovirus K Rec forms a regulatory loop with MITF that opposes the progression of melanoma to an invasive stage

By Manvendra Singh, Huiqiang Cai, Mario Bunse, Cédric Feschotte, Zsuzsanna Izsvák

Posted 30 May 2020
bioRxiv DOI: 10.1101/2020.05.27.120170 (published DOI: 10.3390/v12111303)

The HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in a number of pathological conditions, including various tumours. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5\_Hs) of HERV-K and on the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5\_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and to an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies. ### Competing Interest Statement The authors have declared no competing interest.

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