Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer.
Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer.
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长链非编码RNA DLGAP1-AS2通过调节Trim21/ELOA/LHPP轴促进结直肠癌的肿瘤发生和转移。
DOI：
10.1186/s12943-022-01675-w
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发表时间：
2022-11-14
期刊：
影响因子：
37.3
通讯作者：
Huang, Zhaohui
中科院分区：
文献类型：
--
作者：
Wang, Xue;Cheng, Han;Zhao, Jing;Li, Jiuming;Chen, Ying;Cui, Kaisa;Tian, Lu;Zhang, Jia;Li, Chaoqun;Sun, Shengbai;Feng, Yuyang;Yao, Surui;Bian, Zehua;Huang, Shenglin;Fei, Bojian;Huang, Zhaohui
长链非编码RNA（lncRNA）的研究集中在其作为致癌基因或肿瘤抑制因子参与致癌作用。然而，大多数lncRNA在结直肠癌（CRC）中的功能和机制仍不清楚。在多个CRC队列中通过定量RT-PCR评估DLGAP 1-AS 2的表达。通过一系列体外和体内试验评估DLGAP 1-AS 2对CRC生长和转移的影响。此外，通过RNA下拉、RNA免疫沉淀、RNA测序、荧光素酶测定、染色质免疫沉淀和拯救实验揭示了DLGAP 1-AS 2在CRC中的潜在机制。我们发现DLGAP 1-AS 2通过与Elongin A（Elongin A）的物理相互作用促进CRC肿瘤的发生和转移，并通过促进包含21（Trim 21）的三重基序介导的Elongin A的泛素化修饰和降解来抑制其蛋白稳定性。特别地，我们揭示了DLGAP 1-AS 2通过抑制LHPP介导的转录激活来降低磷赖氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）的表达，从而阻断LHPP依赖的AKT信号传导途径的抑制。此外，我们还证明DLGAP 1-AS 2被切割和多聚腺苷酸化特异性因子（CPSF 2）和切割刺激因子（CSTF 3）结合并稳定。DLGAP 1-AS 2是一种有前景的预后生物标志物，其发现揭示了CRC分子发病机制的新维度，并为该疾病提供了前瞻性的治疗靶点。在线版本包含补充材料，可通过10.1186/s12943-022-01675-w获得。
Long noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. The expression of DLGAP1-AS2 was assessed by quantitative RT-PCR in multiple CRC cohorts. The impacts of DLGAP1-AS2 on CRC growth and metastasis were evaluated by a series of in vitro and in vivo assays. Furthermore, the underlying mechanism of DLGAP1-AS2 in CRC was revealed by RNA pull down, RNA immunoprecipitation, RNA sequencing, luciferase assays, chromatin immunoprecipitation, and rescue experiments. We discovered that DLGAP1-AS2 promoted CRC tumorigenesis and metastasis by physically interacting with Elongin A (ELOA) and inhibiting its protein stability by promoting tripartite motif containing 21 (Trim21)-mediated ubiquitination modification and degradation of ELOA. In particular, we revealed that DLGAP1-AS2 decreases phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) expression by inhibiting ELOA-mediated transcriptional activating of LHPP and thus blocking LHPP-dependent suppression of the AKT signaling pathway. In addition, we also demonstrated that DLGAP1-AS2 was bound and stabilized by cleavage and polyadenylation specificity factor (CPSF2) and cleavage stimulation factor (CSTF3). The discovery of DLGAP1-AS2, a promising prognostic biomarker, reveals a new dimension into the molecular pathogenesis of CRC and provides a prospective treatment target for this disease. The online version contains supplementary material available at 10.1186/s12943-022-01675-w.
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