Cancer Initiation: June 2013

Saturday, June 15, 2013

The emerging connection between cancer epidemiology and environmental toxcants

This note is largely a review, explanation, and extension of the review produced by Su et. al. [1]. Until recent advances in our understanding of cancer initiation, the connection between cancer and environmental contaminants remained elusive. The presumption for a proposed carcinogen was that it had the ability to integrate into, disrupt, or mutate DNA. As such, the carcinogen would create the heritable changes in cellular progeny that we observe in cancer. On the other hand, many suspected carcinogens such as methyl mercury, other heavy metals, and environmental chlorocarbons ( dioxin ) seemed to slide under the radar in terms of their potential role in cancer epidemiology.
  As described by Su et. al., the emerging paradigm change in toxicology falls under the keyword "epigenetics". As described in the reference, the actual mechanisms of epigenetics are very broad, but in the simplest overview, it suffices to say that each (or most) genes in the chromosome have a "switch" mechanism associated with them. Each gene that may be transcribed is associated with a "promoter" region which is upstream of the start of transcription. When a transcription factor specific for that promoter binds to it, a transcription complex is initiated and begins to produce a transcript.
   The process of transcription described above can be blocked. If the promoter, or the region around the TATA box in the animation has an abundance of  "CpG Islands", these dinucleotides can be methylated, and will attract a binding protein ( Methyl CpG Binding Protein, or MeCP2 ).  The pattern of promoter methylation, as well as other epigenetic changes associated with chromatin, are the drivers of cell differentiation as cells evolve from stem cells to differentiated somatic cells.
  New high speed laboratory tools that can rapidly access the methylation patterns of a cell samples DNA have given researchers a new view of cancer causes. One such gene is retinoblastoma. Rb, or pRb was one of the first known genes associated with cancer, and is known as a key regulator of the cell cycle. In a rare occurrence in science, a long accepted hypothesis may be changed. Initial study of  pRB led to what is known as the "two hit hypothesis". More recently, it has been observed that pRb may be more often associated with epigenetic changes than genetic changes[2]. Likewise, another newsworthy gene, BRCA1 has been shown to be a largely epigenetic problem associated with inappropriate methylation of a checkpoint gene.[3].
  Moving back to the original theme of the article, although  methyl mercury and heavy metals have been difficult to connect to DNA mutations, they have been fairly easy to connect with the maintenance of methylation patterns associated with promoters.[4].
  Although Su [1] and others describe "progressive global hypomethylation" as an epigenetic description of carcinogenesis I have not yet seen the presumptive cause speculated upon. At this juncture, it seems to be an increasingly small jump, so lets just go ahead and make it. The term global hypomethylation means that as the stage of a cancer progresses, the overall number of methylated genes declines. As mentioned in Su et. al.,  methylation of CpG islands is maintained by two DNA methyltransferases, DNMT1 and DNMT3.
When the cell divides, he duplicate copy of the DNA must have the methylation patterns copied from the template strand. This is the job of DNMT1. There must be a checkpoint system in place to make sure that progression through the cell cycle is halted until not only DNA synthesis, but methylation pattern duplication is complete. That simple sentence seems to never be said, as it is too speculative, but at this juncture, it is increasingly obvious. For the sake of education and communication, the term incomplete epigenetic pattern duplication due to check point loss is infinitely less cryptic than progressive global hypomethylation  as it is typically referred to in clinical literature.
  There is one last catch. As methylation patterns are lost globally, they can also be inappropriately gained,  by new or "de novo" methylation, New methylation is by DNMT3. Perhaps the confusion here, for the uninitiated, is that de novo methylation can occur as a result of global hypomethylation. Many, if not most transcripts have antisense partners, or "mirrors". They consist of short non coding RNAs called microRNAs or miRNA. The job of a micro rna appears to be to shut down a gene that is no longer appropriate as differentiation continues.  When a micro RNA is transcribed, it finds its complementary partner and forms a silencing complex. This is also called RNA interference. This process, mediated by DROSHA and DICER leads to a complex of  RNA and proteins that will to to the nucleus, find the appropriate gene and silence it by recruiting and mediating DNMT3.
  There is also quite probably the case where antisense microRNAs implement a "surveillance" system on transcripts. That is,  a transcript and its antisense partner are both transcribed, and they do not bind due to secondary structure considerations associated with the sense transcript. If the sense strand loses secondary structure stability due to mutations in the sequence, or un-natural contaminants in the system, the sense strand binds with the antisense strand and shuts down the gene by activating an RNA interference response.
  The "surveillance hypothesis" explains why either germline mutations or environmental toxins could lead to the inappropriate methylation and shut down of a tumor suppressor gene like pRB or BRCA1/2.

[1]  Su LJ, Mahabir S, Ellison GL, McGuinn LA, Reid BC
Epigenetic Contributions to the Relationship between Cancer and Dietary
 Intake of Nutrients, Bioactive Food Components, and Environmental Toxicants.
Front Genet. 2011;2:91.  [PubMed] [Full Text]

[2] Domenico Mastrangelo, Cosimo Loré, Giovanni Grasso
Retinoblastoma as an Epigenetic Disease: A Proposal
JCT> Vol.2 No.3, August 2011 [Full Text]

[3] Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE.
Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer.
Breast Cancer Res. 2006;8(4):R38. [Full Text]

[4] Baccarelli and V. Bollati
Epigenetics and environmental chemicals
Curr Opin Pediatr. 2009 April; 21(2): 243–251. [Full Text]