Selective changes of retroelement expression in human prostate cancer

Abstract

Retroelements constitute a large part of the human genome. These sequences are mostly silenced in normal cells, but genome-wide DNA hypomethylation in cancers might lead to their re-expression. Whether this re-expression really occurs in human cancers is largely unkown. We therefore investigated expression and DNA methylation of several classes of retroelements in human prostate cancer tissues and cell lines by quantitative reverse transcription-polymerase chain reaction and pyrosequencing, respectively. The most striking finding was strong and generalized increased expression of the HERV-K_22q11.23 provirus in cancers, including de novo expression of a spliced accessory Np9 transcript in some tumors. In parallel, DNA methylation in the long terminal repeat (LTR) decreased. Conversely, HERVK17 expression was significantly diminished in cancer tissues, but this decrease was unrelated to LTR methylation. Expression of both proviruses was restricted to androgen-responsive prostate cancer cell lines and LTRs sequences containing steroid hormone-responsive elements bound the androgen receptor and conferred androgen responsiveness to reporter constructs. Expression of LINE-1 5'-untranslated region (UTR) and 3'-UTR sequences in prostate cancers rather decreased, despite significant hypomethylation of the internal LINE-1 promoter. Increased expression of the young AluYa5 and AluYb8 families was restricted to individual tumors. Our findings demonstrate a surprising specificity of changes in expression and DNA methylation of retroelements in prostate cancer. In particular, LINE-1 hypomethylation does not lead to generalized overexpression, but specific human endogenous retrovirus-K proviruses display conspicuous changes in their expression hinting at significant functions during prostate carcinogenesis.

Prostate Cancer Progression Correlates with Increased Humoral Immune Response to a Human Endogenous Retrovirus GAG Protein

“…It is not clear whether the HERV-K 5 0 LTR region alone is sufficient to activate EVT1 expression in these patients. However, our results suggest that the 5 0 LTR promoter region from HERV-K not only is active but can also increase expression in response to androgen hormone stimulation, in accordance with previous findings (37). Taken together, these findings highlight the importance of HERV-K activity in prostate cancer.…”

“…We observed that the DNA methylation status of the HERV-K promoter region (LTR) contributes to GAG-HERV-K expression in cancer cell lines. In accordance with our findings, HERV-K from chromosome 22q11.23 was recently observed to be highly expressed in prostate cancer samples and the expression was dependent on LTR region demethylation (37). Nevertheless, methylation is just one of several mechanisms that impact chromatin structure and gene expression, and it is possible that some of the heterogeneity in GAG-HERV-K expression observed among cancer cell lines may relate to differences in other possible pathways (acetylation, etc.)…”

“…A recent article showed that HERV-K ch22q11.23 is preferentially expressed in hypomethylated prostate cancer cell lines and primary prostate tissue samples (37). We confirmed these observations by showing that the HERV-K promoter region (5 0 LTR) of GAG-HERV-K negative cell lines (LNCaP and PC-3) was hypermethylated when compared with positive cell line VCaP (Fig.…”

“…Cell lines were derived at Memorial Sloan-Kettering Cancer Center or purchased from American Type Culture Collection. All human cell lines were maintained in RPMI containing 10% FBS, 1% L-glutamine at 37 C in a 5% CO 2 atmosphere.…”

Do the Human Endogenous Retroviruses Play a Role in Colon Cancer?

“…[45][46][47][48] In particular, the detection of RNA transcripts of HERVs was described in various human tissues and cancer cells. 49,50 LTRs are usually oriented opposite to the transcription direction of the corresponding host genes and the antisense transcripts affect the partner gene functions, by modifying both the transcriptional and posttranscriptional regulation processes. [51][52][53][54][55][56][57][58] LTRs may also promote cellular transformation by cis activation of downstream oncogenes, and the repetitive nature of HERVs provides an ideal substrate for nonallelic homologous DNA recombination, which results in a variety of germline chromosomal rearrangements, leading to human genetic disorders and cellular transformation of somatic cells.…”