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

Abstract

In the human genome, HERV-K(HML2) is the most recently endogenized retrovirus 42 Through its interaction with CRM1 nuclear export factor [4, 6], Rec is involved in exporting un-43 spliced HERV-K RNA from the nucleus [3, 7]. In addition, Rec can directly modulate cell signalling 44 via binding to the promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor of 45 the c-MYC proto-oncogene [8]. Rec also binds the TZFP (testicular zinc-finger protein) and the hSGT 46 2 of 23 (human small glutamine-rich tetratricopeptide repeat protein), which are transcriptional repressors 47 of the androgen receptor [9, 10]. While it is evident that Rec must have first evolved to facilitate 48 HERV-K replication, there is speculation that the protein may have been coopted for physiological 49 function, such as spermatogenesis [6, 11] and defence against viral infections in the early human 50 embryo [12]. 51It has been reported that at least 18 HERV-K genomic loci can be transcribed in healthy human 52 tissues and express potentially-coding Rec or Np9 mRNAs (alone or in combination with retroviral 53 genes), though the landscape of transcribed HERV-K loci differs considerably between cell/tissue 54 types [13]. Rec RNA/protein expression has been observed in human embryonic tissues, placenta and 55 retina [14, 15]. Interestingly, HERV-K is expressed in both germinal-and pluripotent stem cells, 56 providing a special link between these cell types [16]. While HERV-K transcription has been observed 57 at low levels in various normal tissues, it is strongly induced upon environmental stress, such as 58 ultraviolet irradiation (e.g. UVB and UVC), starvation or viral infection that may manifest the global 59 DNA hypomethylation [17][18][19][20][21]. Furthermore, many studies have reported robust mRNA 60 upregulation of several genomic loci of HERV-K in various disease states, including certain 61 autoimmune diseases and a number of cancers, especially lung, breast cancers, germ cell tumours 62 and melanoma [18, 22, 23] and reviewed in [24, 25]. Moreover, transcriptional activation and 63 translation of various HERV-K products [22, 26] and even virus-like particles have been observed in 64 certain cancer cells such as teratoma, embryonic carcinoma and melanomas [3,[27][28][29]. 65Whether and how the overexpression of HERV-K products may contribute to the etiology or 66 progression of these diseases has been the subject of many studies, debates, and speculations. Several 67 mechanisms have been proposed by which HERV-K might contribute to disease. The activated LTRs 68 could act as alternative promoters and de-regulate tumor suppressor genes or proto-oncogenes 69 (reviewed in [35, 36]). Furthermore, the Env protein of HERV-K, via its fusogenic property, is capable 70 to induce cell-cell fusion and could therefore contribute to tumour invasiveness [18, 37, 38]. Env could 71 also have oncogenic properties through direct interference with cellular signalling pathways (e.g. 72RSS/MEK/ERK) [39, 40]. Indeed, the overexpressi...

Active endogenous retroviral elements in human pluripotent stem cells play a role in regulating host gene expression

“…As dominant of transposable elements, the amplification of LTRs is considered to be harmful to genome stability ( 1 ), therefore, in most situation, LTRs are silenced by various repressive epigenetic mechanisms, such as DNA methylation, H3K9me3, PRC1/2 complex and piwi/piRNA pathway ( 2–6 ). LTRs are involved in many pathological processes, such as neurodegenerative diseases ( 7–9 ), cancer progression ( 10 , 11 ) and inflammatory bowel disease ( 12 ). In addition, LTRs are also involved in normal biological processes, illustrated by the recent report that species-specific LTRs shape its specific early embryonic development process and are essential for embryonic development ( 13 ).…”

Analysing the HERV-K env, np9, rec and gag expression in cervical tissues

“…Indeed, we confirmed the purity of RNA, observing the 5S, 18S and 28S bands. In this study, DNaseI (Invitrogen, Carlsbad, CA, USA) was employed to remove DNA contamination [ 16 , 17 ].…”

“…The melt curve was between 60 ° C and 95 ° C. GAPDH housekeeping gene was used as an internal control, and based on 2 – ΔΔct expression formula, the values for the relative quantification were calculated. The list of primers was summarized in Table 2 [ 16 , 17 ].…”

Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications

“…ERK‐6 locus on 7p22.1 [HERV‐K(HML‐2.HOM)] presents particular interest and is a promising diagnostic biomarker since its transcription was found to be melanoma‐specific and lack thereof characterized healthy melanocytes 75 . Transcriptional balance of the HERV‐K (HML‐2) proteins seems to be an important regulator between the proliferative and the invasive state of melanoma, and the Melanocyte Inducing Transcription Factor (MIFT) plays an important part probably through its binding to the HERV‐K (HML‐2) LTR5H 76 . In fact, the binding of MIFT to the LTR5H leads to the upregulation of Rec expression and enhances the proliferative behavior in melanoma cells, while at the same time Rec knock‐down cells demonstrated a reduced transcription of MIFT, upregulation of Env and Gag expression, increased epithelial‐to‐mesenchymal transition and development of invasive behavior and metastatic features 76 .…”

“…Transcriptional balance of the HERV‐K (HML‐2) proteins seems to be an important regulator between the proliferative and the invasive state of melanoma, and the Melanocyte Inducing Transcription Factor (MIFT) plays an important part probably through its binding to the HERV‐K (HML‐2) LTR5H 76 . In fact, the binding of MIFT to the LTR5H leads to the upregulation of Rec expression and enhances the proliferative behavior in melanoma cells, while at the same time Rec knock‐down cells demonstrated a reduced transcription of MIFT, upregulation of Env and Gag expression, increased epithelial‐to‐mesenchymal transition and development of invasive behavior and metastatic features 76 . Additionally, significant Env presence was found in melanoma tissue samples compared to other normal control tissues and CAR T‐cells targeting HERV‐K Env demonstrated promising results in a mouse xenograft model 77 …”