Downregulation of Wnt7a by DNMT1: Lung tissue responses to cigarette smoke

Jeffrey Serrill, DNMT1, Wnt7a, lung cancer progression, cigarette smoke

Recently, researchers from the University of Colorado School of Medicine presented evidence which sheds some light on the biochemical mechanisms which underlie the development and progression of non-small cell lung cancer (NSCLC). Through their work, which was published in PLoS One in early March, they demonstrate that Wnt7a, a previously identified tumor suppressor gene, appears to be downregulated in these lung cancer tissues by a specific DNA methyltransferase. Though the general downregulation of Wnt7a had been previously noted in other publications, the present study provides a specific mechanism through which this modulation appears to take place. This understanding will undoubtedly prove beneficial for the further research and development of therapies directed toward this specific carcinoma.

The Wnt proteins are best known through work which was conducted on D. melanogaster (fruit fly) development during the late 1970s and early ‘80s, where it was shown that a specific subtype of the protein (Wg) was crucial for the normal embryonic development of these organisms. Since those initial investigations, the identification of a significant number of related WNT genes (and their encoded proteins) has occurred, and the scientific community is still attempting to elucidate the normal physiological roles of many of them. However, it is generally accepted that the majority of these molecules play important roles in normal organismal development, and thus their dysregulation could comprise an important element in the progression of a number of different cancer types.

Wnt7a, the topic of the recently published study, is thought to play a significant regulatory role in the anterior-posterior patterning of the female reproductive tract, and its expression appears to be greatly affected by the presence of certain steroid hormones in these regions during development. In more recent years, it has been identified as a potential regulator of normal epithelial homeostasis in lung tissue, and is believed to be downregulated during the development of non-small cell lung carcinomas. It has also been noted that by artificially restoring physiological levels of Wnt7a, NSCLCs lose their transformative characteristics, resulting in decreased proliferative and invasive capacities of cancerous lung tissue.

The methylation of DNA sequences can result in gene silencing due to the inability of transcriptional machinery to access specific segments of the genome. In various carcinomas, the methylation of an array of different tumor suppressor genes can result in the progression of cancer development, and the transcriptional silencing of several of these genes has been used to diagnose these diseases during their early stages. Cigarette smoke has been previously identified as one component which can cause increases in this type of transcriptional silencing, likely through upregulation of at least one of the various DNA-methyltransferase enzymes which exist in normal lung cells.

In the present study, the research team identifies the specific culprit responsible for the abnormal methylation of the WNT7A gene as Dnmt1, a methyltransferase which is normally expressed in virtually all tissue types. Following the identification of Dnmt1 as the regulator of this methylation, the team then incubated NSCLC cells for a number of weeks with a cigarette smoke condensate (CSC) which is used by laboratories to replicate environmental exposure to cigarettes. Their results indicated that the CSC significantly increased physiological levels of Dnmt1 in the cells, explaining why the observed increase in Wnt7a methylation (and thus lower Wnt7a expression) was occurring.

Collectively, these results provide an exciting elucidation of one of the biochemical pathways which likely plays a significant role in the development and progression of non-small cell lung cancers. While a great deal of other gene pathways are also affected by exposure to the carcinogens in cigarette smoke, the availability of therapeutic interventions for such prognoses remains very limited, and this new information could represent a great stride in understanding what type of future therapeutic strategies should be considered. These strategies could potentially involve either the artificial implementation of exogenous Wnt7a or the targeted silencing of the DNMT1 gene to prevent abnormal methylation.

For more information, see the Original Research Article

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