Twist activates miR-22 to suppress estrogen receptor alpha in breast cancer.
Twist activates miR-22 to suppress estrogen receptor alpha in breast cancer.
复制标题
扭曲激活miR-22以抑制乳腺癌中的雌激素受体α。
DOI：
10.1007/s11010-021-04065-w
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发表时间：
2021-06
影响因子：
4.3
通讯作者：
Raman, Venu
中科院分区：
文献类型：
--
作者：
Vesuna, Farhad;Lisok, Ala;van Diest, Paul;Raman, Venu
关键词：
TWIST 1（Twist）是一种碱性螺旋-环-螺旋转录因子，在许多癌症中过表达，并促进肿瘤细胞侵袭、转移和复发。在这项研究中，我们证明Twist上调microRNA 22（miR-22）的表达，进而下调乳腺癌中雌激素受体α（ER）的表达。对一组乳腺癌细胞系中miR-22和Twist表达的初步分析显示Twist和miR-22水平之间存在直接相关性，其中miR-22在ER阴性细胞系中高度表达。过表达Twist导致miR-22水平升高，而下调Twist导致miR-22表达降低。为了表征miR-22的上游启动子区域，我们利用cDNA末端的快速扩增并鉴定了miR-22的转录起始位点和推定的启动子区域。从机制上讲，我们确定Twist与HDAC 1和DNMT 3B组合，通过与近端miR-22启动子中的E-box结合来转录上调miR-22表达。我们还确定了miR-22在3D而不是2D培养中引起生长增加。重要的是，我们观察到乳腺癌分级增加与Twist和miR-22表达之间存在直接相关性。我们还在ER的3 '-UTR区域鉴定了两个潜在的miR-22结合位点，并通过启动子测定证实miR-22通过结合两个靶位点来调节ER表达。这些结果揭示了Twist通过miR-22激活抑制ER的新途径，这可能会促进乳腺癌中的ER阴性表型。
TWIST1 (Twist) is a basic helix-loop-helix transcription factor that is overexpressed in many cancers and promotes tumor cell invasion, metastasis, and recurrence. In this study, we demonstrate that Twist upregulates expression of microRNA 22 (miR-22) which, in turn, downregulates estrogen receptor alpha (ER) expression in breast cancer. Initial analysis of miR-22 and Twist expression in a panel of breast cancer cell lines showed a direct correlation between Twist and miR-22 levels with miR-22 being highly expressed in ER negative cell lines. Overexpressing Twist caused increased miR-22 levels while downregulating it led to decreased miR-22 expression. To characterize the upstream promoter region of miR-22, we utilized rapid amplification of cDNA ends and identified the transcription start site and the putative promoter region of miR-22. Mechanistically, we determined that Twist, in combination with HDAC1 and DNMT3B, transcriptionally upregulates miR-22 expression by binding to E-boxes in the proximal miR-22 promoter. We also established that miR-22 causes an increase in growth in 3D but not 2D cultures. Importantly, we observed a direct correlation between increased breast cancer grade and Twist and miR-22 expression. We also identified two potential miR-22 binding sites in the 3’-UTR region of ER and confirmed by promoter assays that miR-22 regulates ER expression by binding to both target sites. These results reveal a novel pathway of ER suppression by Twist through miR-22 activation that could potentially promote the ER negative phenotype in breast cancers.
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64.8
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