TRF2 cooperates with CTCF for controlling the oncomiR-193b-3p in colorectal cancer
TRF2 cooperates with CTCF for controlling the oncomiR-193b-3p in colorectal cancer
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DOI：
10.1016/j.canlet.2022.215607
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发表时间：
2022-03-03
期刊：
影响因子：
9.7
通讯作者：
Biroccio, Annamaria
中科院分区：
文献类型：
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作者：
Dinami, Roberto;Petti, Eleonora;Biroccio, Annamaria
端粒重复序列结合因子2(TRF2)是参与端粒完整性的关键蛋白，在几种人类癌症中过度表达，促进肿瘤的形成和发展。最近，在端粒外也发现了TRF2，在那里它可以影响基因的表达。在这里，我们提供了TRF2能够调节微小RNAs(MiRNAs)的表达的证据，microRNAs是人类肿瘤中改变的小的非编码RNA。在TRF2调控的miRNAs中，我们关注的是miR-193B-3p，这是一种从癌症基因组图谱数据库中获得的与结直肠癌患者TRF2表达正相关的癌基因iRNA。在机制水平上，miR-193B-3p的表达调控需要TRF2与染色质组织因子CTCF的协同作用。我们发现CTCF与TRF2在物理上相互作用，从而驱动TRF2在miR-193B-3P宿主基因上游的结合位点上的正确定位。TRF2与识别区域的结合是促进miR-193b3p表达所必需的，miR-193b3p反过来抑制肿瘤抑制甲基转移酶SUV39H1的翻译，促进肿瘤细胞的增殖。在患者中证实了miR-193B-3p致癌特性的翻译相关性，其中TRF2和miR-193B-3p之间的关联具有预后价值。
The Telomeric Repeat binding Factor 2 (TRF2), a key protein involved in telomere integrity, is over-expressed in several human cancers and promotes tumor formation and progression. Recently, TRF2 has been also found outside telomeres where it can affect gene expression. Here we provide evidence that TRF2 is able to modulate the expression of microRNAs (miRNAs), small non-coding RNAs altered in human tumors. Among the miRNAs regulated by TRF2, we focused on miR-193b-3p, an oncomiRNA that positively correlates with TRF2 expression in human colorectal cancer patients from The Cancer Genome Atlas dataset. At the mechanistic level, the control of miR-193b-3p expression requires the cooperative activity between TRF2 and the chromatin organization factor CTCF. We found that CTCF physically interacts with TRF2, thus driving the proper positioning of TRF2 on a binding site located upstream the miR-193b-3p host-gene. The binding of TRF2 on the identified region is necessary for promoting the expression of miR-193b3p which, in turn, inhibits the translation of the oncosuppressive methyltransferase SUV39H1 and promotes tumor cell proliferation. The translational relevance of the oncogenic properties of miR-193b-3p was confirmed in patients, in whom the association between TRF2 and miR-193b-3p has a prognostic value.