Identification of novel sense and antisense transcription at the TRPM2 locus in cancer.
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.
Orfanelli
Ugo
U
DIBIT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Wenke
Ann-Kathrin
AK
Doglioni
Claudio
C
Russo
Vincenzo
V
Bosserhoff
Anja Katrin
AK
Lavorgna
Giovanni
G
D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D050053:TRPM Cation Channels / Q000235:genetics*; D014158:Transcription, Genetic
D016375:Antisense Elements (Genetics); D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D020169:Caspases