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

Author

Listed:
  • 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
    Cancer Research Center, Medical College of Georgia, Georgia Regents University)

  • Huidong Shi

    (Medical College of Georgia, Georgia Regents University
    Cancer Research Center, 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
    Cancer Research Center, Medical College of Georgia, Georgia Regents University)

  • Suash Sharma

    (Medical College of Georgia, Georgia Regents University
    Cancer Research Center, Medical College of Georgia, Georgia Regents University)

  • Vadivel Ganapathy

    (Medical College of Georgia, Georgia Regents University
    Cancer Research Center, 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
    Cancer Research Center, Medical College of Georgia, Georgia Regents University)

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.

Suggested Citation

  • Rajneesh Pathania & Sabarish Ramachandran & Selvakumar Elangovan & Ravi Padia & Pengyi Yang & Senthilkumar Cinghu & Rajalakshmi Veeranan-Karmegam & Pachiappan Arjunan & Jaya P. Gnana-Prakasam & Fulzel, 2015. "DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7910
    DOI: 10.1038/ncomms7910
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    Cited by:

    1. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Dae Joong Kim & Swetha Anandh & Jamie L. Null & Piotr Przanowski & Sanchita Bhatnagar & Pankaj Kumar & Sarah E. Shelton & Erin E. Grundy & Katherine B. Chiappinelli & Roger D. Kamm & David A. Barbie &, 2023. "Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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