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UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor

Oncogene volume 36, pages 5497–5511 (2017)Cite this article

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Abstract

UTX is implicated in embryonic development and lineage specification. However, how this X-linked histone demethylase contributes to the occurrence and progression of breast cancer remains to be clarified. Here we report that UTX is physically associated with estrogen receptor (ER) and functions in ER-regulated transcription. We showed that UTX coordinates with JHDM1D and CBP to direct H3K27 methylation–acetylation transition and to create a permissive chromatin state on ER targets. Genome-wide analysis of the transcriptional targets of UTX by ChIP-seq identified a set of genes such as chemokine receptor CXCR4 that are intimately involved in breast cancer tumorigenesis and metastasis. We demonstrated that UTX promotes the proliferation and migration of ER+ breast cancer cells. Interestingly, UTX itself is transactivated by ER, forming a feed-forward loop in the regulation of hormone response. Indeed, UTX is upregulated during ER+ breast cancer progression, and the expression level of UTX is positively correlated with that of CXCR4 and negatively correlated with the overall survival of ER+ breast cancer patients. Our study identified a feed-forward loop between UTX and ER in the regulation of hormonally responsive breast carcinogenesis, supporting the pursuit of UTX as an emerging therapeutic target for the intervention of certain ER+ breast cancer with specific epigenetic vulnerability.

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Gene Expression Omnibus

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Acknowledgements

This work was supported by grants (973 Program: 2014CB542004 to JL and YS) from the Ministry of Science and Technology of China, and grants (31371301 and 81572771 to JL and 91219201 and 81130048 to YS) from the National Natural Science Foundation of China.

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The UTX ChIP-seq data have been deposited to the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/), the accession number is GSE96996.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    G Xie, Y Zhang, W Li, S Liu, Z Chen, B Xu, J Yang, L He, Z Zhang, T Jin, X Yi, L Sun, Y Shang & J Liang

  2. Department of Biochemistry and Molecular Biology, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    X Liu & Y Shang

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Y Shang

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Xie, G., Liu, X., Zhang, Y. et al. UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor. Oncogene 36, 5497–5511 (2017). https://doi.org/10.1038/onc.2017.157

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