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Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer

SIMPLE SUMMARY: Genomic 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)...

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Autores principales: Skaar, David A., Dietze, Eric C., Alva-Ornelas, Jackelyn A., Ann, David, Schones, Dustin E., Hyslop, Terry, Sistrunk, Christopher, Zalles, Carola, Ambrose, Adrian, Kennedy, Kendall, Idassi, Ombeni, Miranda Carboni, Gustavo, Gould, Michael N., Jirtle, Randy L., Seewaldt, Victoria L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656495/
https://www.ncbi.nlm.nih.gov/pubmed/34885139
http://dx.doi.org/10.3390/cancers13236031
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author Skaar, David A.
Dietze, Eric C.
Alva-Ornelas, Jackelyn A.
Ann, David
Schones, Dustin E.
Hyslop, Terry
Sistrunk, Christopher
Zalles, Carola
Ambrose, Adrian
Kennedy, Kendall
Idassi, Ombeni
Miranda Carboni, Gustavo
Gould, Michael N.
Jirtle, Randy L.
Seewaldt, Victoria L.
author_facet Skaar, David A.
Dietze, Eric C.
Alva-Ornelas, Jackelyn A.
Ann, David
Schones, Dustin E.
Hyslop, Terry
Sistrunk, Christopher
Zalles, Carola
Ambrose, Adrian
Kennedy, Kendall
Idassi, Ombeni
Miranda Carboni, Gustavo
Gould, Michael N.
Jirtle, Randy L.
Seewaldt, Victoria L.
author_sort Skaar, David A.
collection PubMed
description SIMPLE SUMMARY: Genomic 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. ABSTRACT: 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.
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spelling pubmed-86564952021-12-10 Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer Skaar, David A. Dietze, Eric C. Alva-Ornelas, Jackelyn A. Ann, David Schones, Dustin E. Hyslop, Terry Sistrunk, Christopher Zalles, Carola Ambrose, Adrian Kennedy, Kendall Idassi, Ombeni Miranda Carboni, Gustavo Gould, Michael N. Jirtle, Randy L. Seewaldt, Victoria L. Cancers (Basel) Article SIMPLE SUMMARY: Genomic 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. ABSTRACT: 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. MDPI 2021-11-30 /pmc/articles/PMC8656495/ /pubmed/34885139 http://dx.doi.org/10.3390/cancers13236031 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Skaar, David A.
Dietze, Eric C.
Alva-Ornelas, Jackelyn A.
Ann, David
Schones, Dustin E.
Hyslop, Terry
Sistrunk, Christopher
Zalles, Carola
Ambrose, Adrian
Kennedy, Kendall
Idassi, Ombeni
Miranda Carboni, Gustavo
Gould, Michael N.
Jirtle, Randy L.
Seewaldt, Victoria L.
Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title_full Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title_fullStr Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title_full_unstemmed Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title_short Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
title_sort epigenetic dysregulation of kcnk9 imprinting and triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656495/
https://www.ncbi.nlm.nih.gov/pubmed/34885139
http://dx.doi.org/10.3390/cancers13236031
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