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

doi:10.1038/ncomms7910

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 journal › Article

115 Scopus citations

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	https://doi.org/10.1038/ncomms7910
State	Published - Apr 22 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Pathania, R., Ramachandran, S., Elangovan, S., Padia, R., Yang, P., Cinghu, S., Veeranan-Karmegam, R., Arjunan, P., Gnana-Prakasam, J. P., Sadanand, F., Pei, L., Chang, C. S., Choi, J. H., Shi, H., Manicassamy, S., Prasad, P. D., Sharma, S., Ganapathy, V., Jothi, R., & Thangaraju, M. (2015). DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature communications, 6, [6910]. https://doi.org/10.1038/ncomms7910

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

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, 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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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.",

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AU - Ramachandran, Sabarish

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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

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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.

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