Human Endogenous Retrovirus K Rec forms a Regulatory Loop with MITF that Opposes the Progression of Melanoma to an Invasive Stage

Viruses. 2020 Nov 13;12(11):1303. doi: 10.3390/v12111303.

Abstract

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 several pathological conditions, including various tumors. 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 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) (also known as 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 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.

Keywords: HERV-K; LTR5_Hs; MITF; Rec; invasive; melanoma; proliferative.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression*
  • Endogenous Retroviruses / genetics*
  • Endogenous Retroviruses / metabolism
  • Gene Expression Regulation, Viral
  • Gene Products, env / genetics
  • Gene Products, env / metabolism
  • Gene Products, gag / genetics
  • Gene Products, gag / metabolism
  • Genetic Loci
  • Humans
  • Melanoma / virology*
  • Retroviridae Proteins / genetics*
  • Retroviridae Proteins / metabolism
  • Sequence Analysis, RNA
  • Species Specificity
  • Terminal Repeat Sequences

Substances

  • Gene Products, env
  • Gene Products, gag
  • Retroviridae Proteins