Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer
by
, , and
David A. Skaar
1,†
,
Eric C. Dietze
2,†,
Jackelyn A. Alva-Ornelas
2,†,
David Ann
2,
Dustin E. Schones
2,
Terry Hyslop
3,
Christopher Sistrunk
2
,
Carola Zalles
4,
Adrian Ambrose
2,
Kendall Kennedy
2,
Ombeni Idassi
2,
Gustavo Miranda Carboni
5,
Michael N. Gould
6,‡,
Randy L. Jirtle
1,* and
Victoria L. Seewaldt
2,* 1
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
2
Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA
3
Department of Biostatistics, School of Medicine, Duke University, Durham, NC 27710, USA
4
Department of Pathology, Mercy Hospital, Miami, FL 33133, USA
5
Laboratory of Oncology, Department of Oncology, School of Medicine, University of Tennessee Health Science, Memphis, TN 38163, USA
6
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Deceased.
Cancers 2021, 13(23), 6031; https://doi.org/10.3390/cancers13236031
Submission received: 15 November 2021
/
Accepted: 26 November 2021
/
Published: 30 November 2021
(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of 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) 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.
Keywords:
triple negative breast cancer; KCNK9; epigenetics; imprinting
