ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription
ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription
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ASH2L 通过上调 PAX2 转录参与促进子宫内膜癌进展
DOI：
10.1111/cas.14413
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发表时间：
2020
期刊：
影响因子：
5.7
通讯作者：
Yue Zhao
中科院分区：
文献类型：
--
作者：
Kai Zeng;Yi Wu;Chunyu Wang;Shengli Wang;Hongmiao Sun;Renlong Zou;Ge Sun;Huijuan Song;Wei Liu;Ning Sun;Shan Wei;Wensu Liu;Yingjie Su;Tingting Zhou;Yi Zhang;Yue Zhao
缺失、小或同源异型2-样蛋白（ASH 2L）是多聚体组蛋白甲基转移酶复合物的核心组分，其参与维持活性转录，参与多种癌症，然而ASH 2L在子宫内膜癌（ECa）中的生物学功能和分子机制在很大程度上未知。子宫内膜癌是女性常见的恶性肿瘤，其发病率呈上升趋势。雌激素-ERα信号通路作为一种致癌通路，在子宫内膜癌的发生中起着至关重要的作用。因此，深入探讨ERα介导的ECa基因转录的分子机制，将有助于了解肿瘤的发生发展，并为ECa的治疗寻找新的靶点。在此，我们的研究表明ASH 2L在ECa样本中高度表达，并且ASH 2L的高表达与不良预后呈正相关。此外，我们发现ASH 2L与ERα相关，并且ASH 2L的敲低导致雌激素诱导的靶基因亚组的表达降低，包括配对盒2（PAX 2），ECa中的致癌基因。ASH 2L被募集到PAX 2中的顺式调节元件，从而改变组蛋白H3 K4 me 3和H3 K27 me 3水平，以增强ERα介导的反式激活。最后，ASH 2L的耗竭抑制了子宫内膜癌细胞的增殖和迁移。我们的研究结果表明，ASH 2L参与促进ECa进展，如果不是全部，至少部分，通过上调PAX 2转录。
Absent, small or homeotic 2‐like protein (ASH2L) is a core component of a multimeric histone methyltransferase complex that is involved in the maintenance of active transcription, participating in several cancers, however the biological function and molecular mechanism of ASH2L in endometrial cancer (ECa) are largely unknown. Endometrial cancer is a common malignant tumor in women and the incidence of this cancer is on the rise. Estrogen‐ERα signaling, as an oncogenic pathway, plays a crucial role in endometrial carcinogenesis. Therefore, further exploration of the molecular mechanisms around ERα‐mediated gene transcription in ECa would be helpful to the understanding of tumor development and to finding a new therapeutic target for ECa. Here, our study demonstrated that ASH2L was highly expressed in ECa samples, and higher expression of ASH2L was positively correlated with a poor prognosis. Moreover, we identified that ASH2L associated with ERα and that knockdown of ASH2L resulted in decreased expression of a subset of the estrogen‐induced target genes, including paired box 2 (PAX2), an oncogenic gene in ECa. ASH2L was recruited tocis‐regulatory elements inPAX2, thereby altering histone H3K4me3 and H3K27me3 levels, to enhance ERα‐mediated transactivation. Finally, depletion of ASH2L suppressed endometrial cancer cell proliferation and migration. Our findings suggest that ASH2L participates in the promotion of ECa progression, if not totally at least partially, via upregulation ofPAX2transcription.