lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus
lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus
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DOI：
10.1038/s41418-021-00879-9
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发表时间：
2021-10-04
影响因子：
12.4
通讯作者：
Gao, Peng
中科院分区：
文献类型：
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作者：
Liu, Hai-Ting;Zou, Yong-Xin;Gao, Peng
长非编码RNA（lncRNA）在不同的癌症类型中失调，因此已成为人类癌症发生和进展的重要调节因子。然而，人们对其在胃癌（GC）中的生物学功能和潜在机制仍知之甚少。在这里，通过lncRNA微阵列，我们鉴定了1414个差异表达的lncRNA，其中与非肿瘤胃组织相比，THAP7-AS1在GC组织中显着上调。 THAP7-AS1的高表达与淋巴结转移阳性和较差的预后相关。 SP1是一种转录因子，可以直接结合THAP7-AS1启动子区域并激活其转录。此外，METTL3 对 THAP7-AS1 的 m(6)A 修饰增强了其表达，这取决于“阅读器”蛋白 IGF2BP1 依赖性途径。 THAP7-AS1 促进 GC 细胞进展。从机制上讲，THAP7-AS1通过其1-442 nt序列与CUL4B的1-50氨基酸区域（核定位信号）相互作用，促进核定位信号（NLS）与导入蛋白α1之间的相互作用，并改善CUL4B蛋白进入细胞核，通过CUL4B催化抑制miR-22-3p和miR-320a的表达H2AK119ub1 和 EZH2 介导的 H3K27me3，随后激活 PI3K/AKT 信号通路，促进 GC 进展。此外，LV-sh-THAP7-AS1治疗可以抑制GC生长、侵袭和转移，表明THAP7-AS1可能作为GC治疗的一个有前途的分子靶点。综上所述，我们的结果表明，THAP7-AS1由SP1转录激活，然后由METTL3介导的m6A修饰，通过促进NLS和输入蛋白α1之间的相互作用，然后改善CUL4B蛋白进入细胞核以抑制miR-22-3p和miR-320a的转录来发挥致癌功能。
Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m(6)A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin alpha 1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin alpha 1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.