DNA甲基转移酶1（DNMT1）对于乳腺和癌症干细胞的维持以及肿瘤发生至关重要。
DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.
作者信息
Pathania Rajneesh, Ramachandran Sabarish, Elangovan Selvakumar, Padia Ravi, Yang Pengyi, Cinghu Senthilkumar, Veeranan-Karmegam Rajalakshmi, Arjunan Pachiappan, Gnana-Prakasam Jaya P, Sadanand Fulzele, Pei Lirong, Chang Chang-Sheng, Choi Jeong-Hyeon, Shi Huidong, Manicassamy Santhakumar, Prasad Puttur D, Sharma Suash, Ganapathy Vadivel, Jothi Raja, Thangaraju Muthusamy
机构信息
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
System Biology Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
出版信息
Nat Commun. 2015 Apr 24;6:6910. doi: 10.1038/ncomms7910.
Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.
乳腺干细胞/祖细胞（MaSCs）在青春期和孕期维持乳腺上皮的自我更新。DNA甲基化提供了一种在自我更新过程中维持细胞记忆的潜在表观遗传机制。尽管DNA甲基转移酶（DNMTs）对于胚胎干细胞的维持并非必需，但其在不断更新的乳腺上皮中维持MaSCs和癌症干细胞（CSCs）方面的作用尚不清楚。在此，我们表明DNMT1对于MaSC的维持不可或缺。此外，我们发现DNMT1在乳腺肿瘤中表达升高，而乳腺特异性DNMT1缺失通过限制CSC库保护小鼠免受乳腺肿瘤发生。通过全基因组甲基化研究，我们确定ISL1是DNMT1的直接靶点，在乳腺肿瘤和CSCs中发生高甲基化并下调。乳腺癌细胞中的DNMT抑制或ISL1表达可限制CSC群体。总之，我们的研究揭示了DNMT1在MaSC和CSC维持中的重要作用，并确定DNMT1-ISL1轴为乳腺癌治疗的潜在治疗靶点。
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