Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh 462066, India.
Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11440-11445. doi: 10.1073/pnas.1708447114. Epub 2017 Oct 9.
Aberrant alternative splicing and epigenetic changes are both associated with various cancers, but epigenetic regulation of alternative splicing in cancer is largely unknown. Here we report that the intragenic DNA methylation-mediated binding of Brother of Regulator of Imprinted Sites (BORIS) at the alternative exon of Pyruvate Kinase () is associated with cancer-specific splicing that promotes the Warburg effect and breast cancer progression. Interestingly, the inhibition of DNA methylation, BORIS depletion, or CRISPR/Cas9-mediated deletion of the BORIS binding site leads to a splicing switch from cancer-specific to normal isoform. This results in the reversal of the Warburg effect and the inhibition of breast cancer cell growth, which may serve as a useful approach to inhibit the growth of breast cancer cells. Importantly, our results show that in addition to splicing, BORIS also regulates the alternative splicing of several genes in a DNA methylation-dependent manner. Our findings highlight the role of intragenic DNA methylation and DNA binding protein BORIS in cancer-specific splicing and its role in tumorigenesis.
异常的选择性剪接和表观遗传变化都与各种癌症有关，但癌症中选择性剪接的表观遗传调控在很大程度上是未知的。在这里，我们报告说，内源性 DNA 甲基化介导的 Brother of Regulator of Imprinted Sites (BORIS) 在丙酮酸激酶 () 的选择性外显子上的结合与促进沃伯格效应和乳腺癌进展的癌症特异性剪接有关。有趣的是，抑制 DNA 甲基化、BORIS 耗竭或 CRISPR/Cas9 介导的 BORIS 结合位点缺失导致从癌症特异性 到正常 异构体的剪接转换。这导致沃伯格效应的逆转和乳腺癌细胞生长的抑制，这可能成为抑制乳腺癌细胞生长的一种有用方法。重要的是，我们的研究结果表明，除了 剪接外，BORIS 还以 DNA 甲基化依赖的方式调节几个基因的选择性剪接。我们的发现强调了内源性 DNA 甲基化和 DNA 结合蛋白 BORIS 在癌症特异性剪接及其在肿瘤发生中的作用。
