DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis

Rajneesh Pathania, Sabarish Ramachandran, Selvakumar Elangovan, Ravi Padia, Pengyi Yang, Senthilkumar Cinghu, Rajalakshmi Veeranan-Karmegam, Pachiappan Arjunan, Jaya P. Gnana-Prakasam, Fulzele Sadanand, Lirong Pei, Chang-Sheng Chang, Jeong-Hyeon Choi, Huidong Shi, Santhakumar Manicassamy, Puttur D Prasad, Suash Sharma, Vadivel Ganapathy, Raja Jothi and Muthusamy Thangaraju ()
Additional contact information
Rajneesh Pathania: Medical College of Georgia, Georgia Regents University
Sabarish Ramachandran: Medical College of Georgia, Georgia Regents University
Selvakumar Elangovan: Medical College of Georgia, Georgia Regents University
Ravi Padia: Medical College of Georgia, Georgia Regents University
Pengyi Yang: System Biology Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Senthilkumar Cinghu: System Biology Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Rajalakshmi Veeranan-Karmegam: Medical College of Georgia, Georgia Regents University
Pachiappan Arjunan: Medical College of Georgia, Georgia Regents University
Jaya P. Gnana-Prakasam: Medical College of Georgia, Georgia Regents University
Fulzele Sadanand: Medical College of Georgia, Georgia Regents University
Lirong Pei: Medical College of Georgia, Georgia Regents University
Chang-Sheng Chang: Medical College of Georgia, Georgia Regents University
Jeong-Hyeon Choi: Medical College of Georgia, Georgia Regents University
Huidong Shi: Medical College of Georgia, Georgia Regents University
Santhakumar Manicassamy: Cancer Research Center, Medical College of Georgia, Georgia Regents University
Puttur D Prasad: Medical College of Georgia, Georgia Regents University
Suash Sharma: Medical College of Georgia, Georgia Regents University
Vadivel Ganapathy: Medical College of Georgia, Georgia Regents University
Raja Jothi: System Biology Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Muthusamy Thangaraju: Medical College of Georgia, Georgia Regents University

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7910

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