Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer.
Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer.
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DOI：
10.3390/cancers13236031
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发表时间：
2021-11-30
期刊：
影响因子：
5.2
通讯作者：
Seewaldt VL
中科院分区：
文献类型：
--
作者：
Skaar DA;Dietze EC;Alva-Ornelas JA;Ann D;Schones DE;Hyslop T;Sistrunk C;Zalles C;Ambrose A;Kennedy K;Idassi O;Miranda Carboni G;Gould MN;Jirtle RL;Seewaldt VL
基因组印记是一种遗传形式的父母的起源特定的表观遗传基因调控，是失调的产前营养和环境毒素。在这里，我们发现KCNK 9在乳腺组织中有印记，并确定了控制其印记状态的差异甲基化区域（DMR）。DMR的低甲基化，加上KCNK 9的双等位基因表达，发生在63%的三阴性乳腺癌（TNBC）中。低甲基化和TNBC状态之间的关联在非洲裔美国人中非常显著（p = 0.006），但在高加索人中不显著（p = 0.70）。来自高危女性的TNBC和非癌性乳腺组织中KCNK 9 DMR低甲基化的高频率提供了证据，表明KNCK 9 DMR/TASK 3过表达的低甲基化可能为预防TNBC提供新的靶点。基因组印记是一种遗传形式的父母的起源特定的表观遗传基因调控，是失调的产前营养和环境毒素。KCNK 9编码TASK 3，这是一种pH调节的钾通道膜蛋白，在40%的乳腺癌中过表达。然而，KCNK 9基因扩增在<10%的乳腺癌中表达增加。在这里，我们发现KCNK 9在乳腺组织中有印记，并确定了控制其印记状态的差异甲基化区域（DMR）。DMR的低甲基化，加上KCNK 9的双等位基因表达，发生在63%的三阴性乳腺癌（TNBC）中。低甲基化和TNBC状态之间的关联在非洲裔美国人中非常显著（p = 0.006），但在高加索人中不显著（p = 0.70）。在77%的乳腺癌高危女性的非癌组织中也发现了KCNK 9低甲基化。功能研究表明，KCNK 9基因产物TASK 3调节线粒体膜电位和细胞凋亡敏感性。在来自高风险女性的TNBC细胞和非癌性乳腺上皮细胞中，KCNK 9 DMR的低甲基化预测TASK 3表达和线粒体膜电位增加（p < 0.001）。这是首次在乳腺上皮细胞中鉴定出KCNK 9 DMR，并证明其在乳腺癌中的低甲基化与线粒体膜电位和细胞凋亡抗性的增加相关。来自高风险女性的TNBC和非癌性乳腺组织中KCNK 9 DMR的低甲基化的高频率提供了证据，表明KNCK 9 DMR/TASK 3过表达的低甲基化可以作为风险的标志物和预防TNBC的靶点，特别是在非洲裔美国女性中。
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. 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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