Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Oncogene. 2017 Sep 28;36(39):5497-5511. doi: 10.1038/onc.2017.157. Epub 2017 May 22.
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.
UTX 参与胚胎发育和谱系特化。然而，这种 X 连锁组蛋白去甲基化酶如何促进乳腺癌的发生和发展仍有待阐明。在这里，我们报告 UTX 与雌激素受体（ER）物理结合，并在 ER 调节的转录中发挥作用。我们表明，UTX 与 JHDM1D 和 CBP 协调，以指导 H3K27 甲基化-乙酰化转换，并在 ER 靶标上创建允许的染色质状态。通过 ChIP-seq 对 UTX 的转录靶标进行全基因组分析，确定了一组基因，如趋化因子受体 CXCR4，它们与乳腺癌的发生和转移密切相关。我们证明了 UTX 促进 ER 乳腺癌细胞的增殖和迁移。有趣的是，UTX 本身被 ER 反式激活，在激素反应的调节中形成正反馈环。事实上，UTX 在 ER 乳腺癌进展过程中上调，其表达水平与 CXCR4 的表达水平呈正相关，与 ER 乳腺癌患者的总生存率呈负相关。我们的研究在调控激素反应性乳腺癌发生方面鉴定了 UTX 和 ER 之间的正反馈环，支持将 UTX 作为干预特定具有特定表观遗传脆弱性的 ER 乳腺癌的新兴治疗靶标进行研究。
