Toxicant-induced malignant transformation

· TGI - Cancer, TGI - Epigenetics
Authors

Cells transmit information to the next generation via two distinct ways: genetic and epigenetic.

Chemical modifications to DNA or histone that alters the structure of chromatin without change of DNA nucleotide sequence are known as epigenetics. These heritable epigenetic changes include DNA methylationpost-translational modifications of histone tails (acetylation, methylation, phosphorylation, etc), and higher order packaging of DNA around nucleosomes. Apart from DNA methyltransferases, histone modification enzymes such as histone acetyltransferase, histone deacetylase, and methyltransferase, and microRNAs (miRNAs) all involve in these epigenetic changes.

Epigenetic dysfunction is a known contributor in carcinogenesis, and is emerging as a mechanism involved in toxicant-induced malignant transformation for environmental carcinogens such as arsenicals or cadmium.

In our earlier post we have presented the fact that epigenetic effects may play a role in Cd toxic, particularly carcinogenic effects. 

https://tginnovations.wordpress.com/2012/09/17/cadmium-and-its-epigenetic-effects/

In another study published in Toxicol Sci. 2012 Feb;125(2):412-7. Epub 2011 Nov 23. titled “Analysis of aberrant methylation in DNA repair genes during malignant transformation of human bronchial epithelial cells induced by cadmium.” indicates that DNA methyltransferase genes DNMT1 and DNMT3a overexpression can result in global DNA hypermethylation and silencing of the hMSH2, ERCC1, XRCC1, and hOGG1 genes.

Also suggests that the DNA demethylating agent 5-aza-2′-deoxycytidine could reverse the Cd-induced global DNA hypermethylation, DNMT hyperactivity, and the silencing of hMSH2, ERCC1, XRCC1, and hOGG1 in a time-dependent manner. http://www.ncbi.nlm.nih.gov/pubmed/22112500

We know that DNA methylation is one of the heritable epigenetic changes. Now here we present the “agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation.”

In addition to aberrant DNA methylation of single genes, another manifestation of epigenetic dysfunction in cancer is agglomerative DNA methylation, which can participate in long-range epigenetic silencing that targets many neighboring genes and has been shown to occur in several types of clinical cancers.

Using in vitro model systems of toxicant-induced malignant transformation, the authors found hundreds of aberrant DNA methylation events that emerge during malignant transformation, some of which occur in an agglomerative fashion.

In an arsenite-transformed prostate epithelial cell line, the protocadherin (PCDH), HOXC and HOXD gene family clusters are targeted for agglomerative DNA methylation. The agglomerative DNA methylation changes induced by arsenicals appear to be common and clinically relevant events, since they occur in other human cancer cell lines and models of malignant transformation, as well as clinical cancer specimens. Aberrant DNA methylation in general occurred more often within histone H3 lysine-27 trimethylation stem cell domains.

The authors found a striking association between enrichment of histone H3 lysine-9 trimethylation stem cell domains and toxicant-induced agglomerative DNA methylation, suggesting these epigenetic modifications may become aberrantly linked during malignant transformation.

It suggests that epigenetic dysfunction plays an important role in toxicant-induced malignant transformation.

The study was published in Epigenetics. 2012 Sep 13;7(11)

 Further details can be read at:

http://www.ncbi.nlm.nih.gov/pubmed/22976526?dopt=Abstract

2 Comments

Comments RSS

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: