Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells
Ruitu Lyu,
Xuguo Zhu,
Yinghui Shen,
Lijun Xiong,
Lu Liu,
Hang Liu,
Feizhen Wu,
Christian Argueta,
Li Tan
Affiliations
Ruitu Lyu
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Xuguo Zhu
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Yinghui Shen
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Lijun Xiong
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Lu Liu
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Hang Liu
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Feizhen Wu
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Christian Argueta
Brigham and Women’s Hospital, Harvard Medical School
Li Tan
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University
Aberrant DNA methylation is an epigenetic hallmark of malignant tumours. The DNA methylation level is regulated by not only DNA methyltransferases (DNMTs) but also Ten-Eleven Translocation (TET) family proteins. However, the exact role of TET genes in breast cancer remains controversial. Here, we uncover that the ERα-positive breast cancer patients with high TET2 mRNA expression had better overall survival rates. Consistently, knockout of TET2 promotes the tumorigenesis of ERα-positive MCF7 breast cancer cells. Mechanistically, TET2 loss leads to aberrant DNA methylation (gain of 5mC) at a large proportion of enhancers, accompanied by significant reduction in H3K4me1 and H3K27ac enrichment. By analysing the epigenetically reprogrammed enhancers, we identify oestrogen responsive element (ERE) as one of the enriched motifs of transcriptional factors. Importantly, TET2 loss impairs 17beta-oestradiol (E2)-induced transcription of the epigenetically reprogrammed EREs-associated genes through attenuating the binding of ERα. Taken together, these findings shed light on our understanding of the epigenetic mechanisms underlying the enhancer reprogramming during breast cancer pathogenesis.
