High Positive Correlations between and -/-/- Gene Cluster Overexpression in Multi-Tumor Types Suggest Deregulated Activation of an Bidirectional Promoter.

The gene, also called , is located at the human locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The gene overlaps a critical region of 125 kb covering the gene. The locus encompasses three major tumor suppressors juxtaposed and joined into a gene cluster. encodes splice variants p16-CDKN2A and p14-ARF, and encodes p15-CDKN2B. shares a bidirectional promoter with the gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of and tumor suppressor , and genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes , , and in the great majority of the 17 different cancer types. was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of , and genes. A high positive correlation was identified between levels of expression of and the three tumor suppressors. The strongest positive association was observed with ( < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.