Various genes are known to be regulated by the transcription factor MYC, but the genes that are crucial for its tumorigenic qualities are not clearly defined. Linda Penn and colleagues have found that a non-coding RNA, H19, is a transcriptional target of MYC, and the inhibition of H19 transcription in cancer cells suppresses certain cellular characteristics that are associated with oncogenic transformation.
Despite being first identified as a tumour suppressor, increased expression of H19 is seen in various human cancers, including lung and breast cancer. H19 resides at the same locus as the insulin-like growth factor 2 gene (IGF2), and both of these genes are subject to genomic imprinting — only the maternal allele of H19 and the paternal allele of IGF2 are expressed. Through the combined use of reverse transcriptase (RT)-PCR, northern blotting and allele-specific chromatin immunoprecipitation techniques the authors were able to show that MYC binds to the regulatory regions of the H19 and IGF2 genes. Furthermore, MYC only binds to the non-methylated promoter of the maternal allele of H19 to induce transcription, which indicates that MYC does not alter the imprinting of this gene and that MYC target genes are determined by promoter methylation.
Small interfering RNAs that target H19 in cells derived from lung and breast tumours inhibited anchorage-independent growth and colony formation in vitro — two well-known characteristics of transformed cells. But is there a correlation between the level of MYC expression and H19 expression in these tumours? The authors undertook a large microarray study using 137 node-negative breast cancer samples. Statistical analyses showed that expression levels of MYC were significantly higher in samples with high levels of H19 expression. Similar results were obtained using 240 non-small-cell lung cancer samples, which were analysed using real-time RT-PCR.
The function of non-coding RNAs is unclear, but it is thought that the H19 transcript might regulate RNA translation. So, MYC might indirectly regulate the expression of a number of proteins in tumour cells through the increased expression of H19.