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.
| Original language | English (US) |
|---|---|
| Article number | 6910 |
| Journal | Nature Communications |
| Volume | 6 |
| DOIs | |
| State | Published - Apr 22 2015 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. / 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.
In: Nature Communications, Vol. 6, 6910, 22.04.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis
AU - Pathania, Rajneesh
AU - Ramachandran, Sabarish
AU - Elangovan, Selvakumar
AU - Padia, Ravi
AU - Yang, Pengyi
AU - Cinghu, Senthilkumar
AU - Veeranan-Karmegam, Rajalakshmi
AU - Arjunan, Pachiappan
AU - Gnana-Prakasam, Jaya P.
AU - Sadanand, Fulzele
AU - Pei, Lirong
AU - Chang, Chang Sheng
AU - Choi, Jeong Hyeon
AU - Shi, Huidong
AU - Manicassamy, Santhakumar
AU - Prasad, Puttur D.
AU - Sharma, Suash
AU - Ganapathy, Vadivel
AU - Jothi, Raja
AU - Thangaraju, Muthusamy
PY - 2015/4/22
Y1 - 2015/4/22
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84928799024&partnerID=8YFLogxK
U2 - 10.1038/ncomms7910
DO - 10.1038/ncomms7910
M3 - Article
C2 - 25908435
AN - SCOPUS:84928799024
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6910
ER -