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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.
摘要：
基因组印记是一种遗传形式的亲代特异性表观遗传基因调控，因不良的产前营养和环境毒素而失调。KCNK9编码TASK3，一种pH调节的钾通道膜蛋白，在40％的乳腺癌中过表达。然而,KCNK9基因扩增导致这些乳腺癌中<10%的表达增加。这里,我们发现KCNK9在乳腺组织中被印迹，并确定了控制其印迹状态的差异甲基化区域（DMR）。DMR的低甲基化,再加上KCNK9的双等位基因表达，63%的三阴性乳腺癌（TNBC）发生。在非裔美国人中，低甲基化和TNBC状态之间的关联非常显着（p=0.006），但不是在高加索人（p=0.70）。在77％的高风险患乳腺癌的女性的非癌组织中也发现了KCNK9低甲基化。功能研究表明，KCNK9基因产物，TASK3调节线粒体膜电位和凋亡敏感性。在TNBC细胞和来自高危女性的非癌乳腺上皮细胞中，KCNK9DMR的低甲基化预测增加的TASK3表达和线粒体膜电位(p<0.001)。这是乳腺上皮细胞中KCNK9DMR的首次鉴定，并证明其在乳腺癌中的低甲基化与线粒体膜电位和凋亡抗性的增加有关。KCNK9DMR在TNBC和来自高危女性的非癌乳腺组织中的高频率的低甲基化提供了证据，表明KNCK9DMR/TASK3过表达的低甲基化可以作为风险标志物和预防TNBC的目标。尤其是非洲裔美国女性。
