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, Muthusamy Thangaraju

Research output: Contribution to journalArticle

102 Citations (Scopus)

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 languageEnglish (US)
Article number6910
JournalNature Communications
Volume6
DOIs
StatePublished - Apr 22 2015

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Neoplastic Stem Cells
stem cells
Stem cells
maintenance
Carcinogenesis
Stem Cells
cancer
Maintenance
Breast
Breast Neoplasms
Methyltransferases
methylation
deoxyribonucleic acid
epithelium
Epithelium
breast
Tumors
tumors
mammary glands
DNA

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 journalArticle

Pathania, R, Ramachandran, S, Elangovan, S, Padia, R, Yang, P, Cinghu, S, Veeranan-Karmegam, R, Arjunan, P, Gnana-Prakasam, JP, Sadanand, F, Pei, L, Chang, CS, Choi, JH, Shi, H, Manicassamy, S, Prasad, PD, Sharma, S, Ganapathy, V, Jothi, R & Thangaraju, M 2015, 'DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis', Nature Communications, vol. 6, 6910. https://doi.org/10.1038/ncomms7910
Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S et al. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature Communications. 2015 Apr 22;6. 6910. https://doi.org/10.1038/ncomms7910
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. / DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. In: Nature Communications. 2015 ; Vol. 6.
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