Non-Coding Regions with Oncogenic Properties
Recent advances in epigenetic research and DNA sequencing have revealed that not all cancer-causing mutations occur in genes that encode a specific protein product. Regions that control gene expression, including promoters and enhancers, as well as boundary elements, introns, and miRNAs are all capable of acquiring mutations with oncogenic/tumor suppressant functions.
Oncogenic Promoter/Enhancer Regions
Single point mutations to promoter or enhancer regions are capable of either increasing or suppressing expression of proteins associated with cancer cell transformation. In terms of proto-oncogenes, SNPs to regulatory regions that enhance gene expression can drive tumor cell transformation. For instance, in prostate cancer, point mutations to the regions upstream of SOX9, which bind AP and AP-1 respectively, increase the transcriptional activity of the SOX9 oncogene. Mutations to regulatory regions can also serve as a diagnostic marker even if their function is not yet fully understood. In prostate cancer, the protein PSP94 which is commonly found in semen is either significantly decreased or absent. This protein loss has been linked to multiple mutations upstream of the MSMB gene which encodes this protein. It is theorized that these point mutations block the enhancer function of this region (1).
Current advances in methods of studying epigenetics have shown that hypermethylation of DNA in cis-regulatory regions of specific genes is an established mechanism in tumor cell transformation. About 50% of familial cancers are associated with abnormal hypermethylation of gene promoter regions in germ line cells. Hypermethylation of promoter regions in many tumor suppressor genes, resulting in gene silencing, has been associated with numerous cancer types. For example, hypermethylation of the RASSF1A promoter, which creates a protein that binds to oncogenic forms of the RAS gene, is correlated to tumorigenesis in lung, breast, colon and prostate cancers (2).
Oncogenic/ Tumor Suppressor MicroRNAs
MicroRNAs (miRNAs) are small non-coding RNA molecules consisting of 19-25 nucleotides which serve as post transcriptional regulators of gene expression. They bind to the 3’ untranslated region (UTR) of a target mRNA molecule and either prevent that mRNA from binding to a ribosome or target it directly for degradation. The level of homology between this 3’ UTR and the microRNA determines whether the mRNA is inhibited or destroyed (3). MicroRNAs are thought to regulate at least 30% of the genome (4). MicroRNA-30a (miR-30a) is known to be involved in various biological processes such as development, differentiation, senescence, apoptosis and autophagy. In breast cancer models, miR-30a upregulation correlates with decreased growth, more compact colonies and decreased migratory abilities, all of which suggest it plays a tumor suppressor function. Bioinformatic analysis of miR-30a reveals that it targets Metadherin (MTDH), a protein with a well studied role in the metastatic cascade. In triple negative breast cancers, MTDH activity is negatively correlated to decreased miR-30a expression. Many different types of cancer cells employ mutations in regions encoding miRNA to either repress tumor suppressor genes or overexpress oncogenes (5).
1. Span, L. et al. The Genomic Landscape of Prostate Cancer. Int J Mol Sci. 2013 (14): 10822-10851.
2. Jones, P. & Bailin, S. The Fundamental Role of Epigenetics in Cancer. Nature Reviews. 2002(3):415-429.
3.Carroll AP, Goodall GJ, Liu B. Understanding principles of miRNA target recognition and function through integrated biological and bioinformatics approaches. Wiley Interdisip Rev RNA. 2014(10) 1002-27.
4.Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006(6): 857–866.
5. Zhang, N. et. Al. MicroRNA-30a suppresses breast tumor growth and metastasis by targeting metadherin. Oncogene. 2012:1-10.