A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Inhibition of histone methyltransferase DOT1L silences ER alpha gene and blocks proliferation of antiestrogen-resistant breast cancer cells
Tekijät: Nassa G., Salvati A., Tarallo R., Gigantino V., Alexandrova E., Memoli D., Sellitto A., Rizzo F., Malanga D., Mirante T., Morelli E., Nees M., Åkerfelt M., Kangaspeska S., Nyman T.A., Milanesi L., Giurato G., Weisz A.
Kustantaja: AMER ASSOC ADVANCEMENT SCIENCE
Julkaisuvuosi: 2019
Journal: Science Advances
Tietokannassa oleva lehden nimi: SCIENCE ADVANCES
Lehden akronyymi: SCI ADV
Artikkelin numero: ARTN eaav5590
Vuosikerta: 5
Numero: 2
Sivujen määrä: 14
ISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.aav5590
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/39891215
Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ER alpha) signaling, and ways to block ERa pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ER alpha in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ER alpha and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ER alpha levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ER alpha-positive BCs.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
