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Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.

Ferreira HJ, Heyn H, Garcia del Muro X, Vidal A, Larriba S, Muñoz C, Villanueva A, Esteller M - Epigenetics (2013)

Bottom Line: Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis.Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development.We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines.

View Article: PubMed Central - PubMed

Affiliation: Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research Institute (IDIBELL); Barcelona, Spain; Programme in Experimental Biology and Biomedicine; Centre for Neurosciences and Cell Biology; University of Coimbra; Coimbra, Portugal.

ABSTRACT
Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia. Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development. We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines. Most importantly, these epigenetic lesions occur in a context of piRNA downregulation and loss of DNA methylation of the LINE-1 repetitive sequences, one of the target genomic loci where the PIWI/piRNA machinery acts as a caretaker in non-transformed cells.

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Figure 4. A model for the PIWI/piRNA pathway in germline cells and its disruption in testicular tumors. piRNAs are small non-coding RNAs that are mainly transcribed as single-stranded intergenic RNAs from well-conserved mono- and bi-directional clusters of repetitive elements. These piRNA precursors translocate into the cytoplasm, where they mature into functional piRNAs. The PIWI proteins catalyze a self-amplification loop, “ping-pong” cycle. Their incorporation into the PIWI ribonucleoprotein (piRNP) complex targets repetitive elements through target degradation and epigenetic silencing. In testicular cancer types, piRNA biogenesis and function are disrupted by DNA hypermethylation mediated transcriptional silencing of PIWI-proteins, leading to the expression of germline transposons.
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Figure 4: Figure 4. A model for the PIWI/piRNA pathway in germline cells and its disruption in testicular tumors. piRNAs are small non-coding RNAs that are mainly transcribed as single-stranded intergenic RNAs from well-conserved mono- and bi-directional clusters of repetitive elements. These piRNA precursors translocate into the cytoplasm, where they mature into functional piRNAs. The PIWI proteins catalyze a self-amplification loop, “ping-pong” cycle. Their incorporation into the PIWI ribonucleoprotein (piRNP) complex targets repetitive elements through target degradation and epigenetic silencing. In testicular cancer types, piRNA biogenesis and function are disrupted by DNA hypermethylation mediated transcriptional silencing of PIWI-proteins, leading to the expression of germline transposons.

Mentions: Overall, our results show the existence of cancer specific hypermethylation events in the CpG islands of genes associated with piRNAs that leads to their transcriptional inactivation in testicular cancer. Most importantly, the epigenetic inactivation of PIWI-class protein genes (PIWIL1, PIWIL2, and PIWIL4) and its associated protein TDRD1 in human testicular tumorigenesis occurs in a molecular context characterized by a diminished expression of the piRNAs and the DNA hypomethylation of LINE1, a PIWI/piRNA target sequence. Interestingly, epigenetic disruption of PIWI proteins also occurs in non-genetic infertility syndromes in males7 and there is an epidemiological association between male infertility and testicular cancer.18,19 Thus, the epigenetic disruption of the PIWI/piRNA pathway could be the missing common link in the genesis of both pathologies. A model for the PIWI/piRNA pathway in normal testis and its disruption in testicular tumors is also shown in Figure 4. Although much work lies ahead to understand the role of the PIWI/piRNA machinery in cellular transformation, the current work provide intriguing clues for further developments and discoveries in this area.


Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.

Ferreira HJ, Heyn H, Garcia del Muro X, Vidal A, Larriba S, Muñoz C, Villanueva A, Esteller M - Epigenetics (2013)

Figure 4. A model for the PIWI/piRNA pathway in germline cells and its disruption in testicular tumors. piRNAs are small non-coding RNAs that are mainly transcribed as single-stranded intergenic RNAs from well-conserved mono- and bi-directional clusters of repetitive elements. These piRNA precursors translocate into the cytoplasm, where they mature into functional piRNAs. The PIWI proteins catalyze a self-amplification loop, “ping-pong” cycle. Their incorporation into the PIWI ribonucleoprotein (piRNP) complex targets repetitive elements through target degradation and epigenetic silencing. In testicular cancer types, piRNA biogenesis and function are disrupted by DNA hypermethylation mediated transcriptional silencing of PIWI-proteins, leading to the expression of germline transposons.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928173&req=5

Figure 4: Figure 4. A model for the PIWI/piRNA pathway in germline cells and its disruption in testicular tumors. piRNAs are small non-coding RNAs that are mainly transcribed as single-stranded intergenic RNAs from well-conserved mono- and bi-directional clusters of repetitive elements. These piRNA precursors translocate into the cytoplasm, where they mature into functional piRNAs. The PIWI proteins catalyze a self-amplification loop, “ping-pong” cycle. Their incorporation into the PIWI ribonucleoprotein (piRNP) complex targets repetitive elements through target degradation and epigenetic silencing. In testicular cancer types, piRNA biogenesis and function are disrupted by DNA hypermethylation mediated transcriptional silencing of PIWI-proteins, leading to the expression of germline transposons.
Mentions: Overall, our results show the existence of cancer specific hypermethylation events in the CpG islands of genes associated with piRNAs that leads to their transcriptional inactivation in testicular cancer. Most importantly, the epigenetic inactivation of PIWI-class protein genes (PIWIL1, PIWIL2, and PIWIL4) and its associated protein TDRD1 in human testicular tumorigenesis occurs in a molecular context characterized by a diminished expression of the piRNAs and the DNA hypomethylation of LINE1, a PIWI/piRNA target sequence. Interestingly, epigenetic disruption of PIWI proteins also occurs in non-genetic infertility syndromes in males7 and there is an epidemiological association between male infertility and testicular cancer.18,19 Thus, the epigenetic disruption of the PIWI/piRNA pathway could be the missing common link in the genesis of both pathologies. A model for the PIWI/piRNA pathway in normal testis and its disruption in testicular tumors is also shown in Figure 4. Although much work lies ahead to understand the role of the PIWI/piRNA machinery in cellular transformation, the current work provide intriguing clues for further developments and discoveries in this area.

Bottom Line: Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis.Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development.We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines.

View Article: PubMed Central - PubMed

Affiliation: Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research Institute (IDIBELL); Barcelona, Spain; Programme in Experimental Biology and Biomedicine; Centre for Neurosciences and Cell Biology; University of Coimbra; Coimbra, Portugal.

ABSTRACT
Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia. Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development. We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines. Most importantly, these epigenetic lesions occur in a context of piRNA downregulation and loss of DNA methylation of the LINE-1 repetitive sequences, one of the target genomic loci where the PIWI/piRNA machinery acts as a caretaker in non-transformed cells.

Show MeSH
Related in: MedlinePlus