Identification of novel sense and antisense transcription at the TRPM2 locus in cancer

Abstract

It has been proposed that in cancer, where the bulk of the genome becomes hypomethylated, there is an increase in transcriptional noise that might lead to the generation of antisense transcripts that could affect the function of key oncosuppressor genes, ultimately leading to malignant transformation. Here, we describe the computational identification of a melanoma-enriched antisense transcript, TRPM2-AS, mapped within the locus of TRPM2, an ion channel capable of mediating susceptibility to cell death. Analysis of the TRPM2-AS genomic region indicated the presence in the same region of another tumor-enriched TRPM2 transcript, TRPM2-TE, located across a CpG island shared with TRPM2-AS. Quantitative PCR experiments confirmed that TRPM2-AS and TRPM2-TE transcripts were up-regulated in melanoma, and their activation was consistent with the methylation status of the shared CpG island. Functional knock-out of TRPM2-TE, as well as over-expression of wild-type TRPM2, increased melanoma susceptibility to apoptosis and necrosis. Finally, expression analysis in other cancer types indicated that TRPM2-AS and TRPM2-TE over-expression might have an even wider role than anticipated, reinforcing the relevance of our computational approach in identifying new potential therapeutic targets.

Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

“…We anticipate this TRPM2 nuclear translocation is a more general phenomenon as we also have observed it in other types of cancer cells (data not shown). It has been reported that two fragments (sense and antisense transcriptions) of TRPM2 are specifically expressed in cancer cells, 3 as our PCR and antibody targeted the C-terminus (exons 30-32, exon 25, respectively) it will be very interesting to see if the nuclear expressed TRPM2 represent or include the TRPM2 fragment of the sense transcription. If so, the cancerspecific transcription will create two functionally important fragment proteins-the antisense fragments inhibit the normal Ca 2 þ transport function of TRPM2 and the sense fragment conducts enzymatic function in the nucleus simultaneously.…”

“…1 The function of TRPM2 in cancer cells has recently been investigated. 2,3 Using a cDNA array technique, significantly increased TRPM2 mRNA expression has been observed in prostate cancer tissues and cell lines in comparison with normal prostate tissues (http:/ /www.ncbi.nlm.nih.gov/projects/geo/gds).…”

Genome-Wide Characterization of Circulating Tumor Cells Identifies Novel Prognostic Genomic Alterations in Systemic Melanoma Metastasis

“…Four of these 5 genes have been reported in cancer or have been implicated in cell adhesion and metastasis. TRPM2 is a calcium channel activated by oxidative stress that regulates susceptibility to cell death (30 -33 ) and has been implicated in prostate cancer (32 ) and melanoma (33 ). In a recent report by Orfanelli et al on aberrant sense and antisense transcripts derived from global hypomethylation studies in melanoma, several transcripts within the TRPM2 locus were enriched in melanoma (33 ).…”

Identification of biomarkers for metastatic osteosarcoma based on DNA microarray data

“…TRPM2 mRNA was found in many primary breast tumors, but no apparent relationship to survival [51]. Besides, overexpression of TRPM2 increased susceptibility of melanoma to apoptosis [52]. Based on these conclusions, we speculate TRPM2 may play a critical role in the metastasis of OS.…”