Abstract
Simple SummaryGenomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. Here, we showed that KCNK9 is imprinted in breast tissue and identified the differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). The high frequency of KCNK9 DMR hypomethylation in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may provide a new target for prevention of TNBC.Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that KCNK9 is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the KCNK9 gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the KCNK9 DMR predicts for increased TASK3 expression and mitochondrial membrane potential (p < 0.001). This is the first identification of the KCNK9 DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the KCNK9 DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
Highlights
Epigenetic adaptations in response to in utero nutritional and environmental factors are hypothesized to play an important role in developmental plasticity and human disease susceptibility [1,2,3]
The relationship between DNA methylation and condensed chromatin structure is consistent with a model in which methylation at the differentially methylated region (DMR) silences gene expression by impacting chromatin accessibility and preventing transcription factor binding
Given that imprinting is dysregulated by poor nutrition and environmental toxicants, our findings provide a potential mechanistic link between disparities and triple-negative breast cancers (TNBC) in African-American women who do not have germline BRCA1 mutations
Summary
Epigenetic adaptations in response to in utero nutritional and environmental factors are hypothesized to play an important role in developmental plasticity and human disease susceptibility [1,2,3]. Environmental factors that alter early nutrition and/or SAM production can potentially influence adult disease risk by altering CpG methylation at critically important, epigenetically labile regulatory regions [4,5]. Genomic imprinting is an inherited form of parent-of-origin dependent epigenetic gene regulation that renders autosomal genes functionally haploid in a species, developmental stage, and tissue dependent manner [6,7]. There is evidence that epigenetic modifications in the genome link environmental exposures to adult disease susceptibility [5,8,9,10,11], including cancer [12,13,14,15]. Disease susceptibility due to epigenetic deregulation has specific windows of vulnerability, including embryogenesis, puberty, pregnancy, and old age [5,18,19,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
