Multiple G-quadruplexes in the LMNA promoter regulate LMNA variant 6 transcription and promote colon cancer cell growth
Multiple G-quadruplexes in the LMNA promoter regulate LMNA variant 6 transcription and promote colon cancer cell growth
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DOI：
10.1016/j.bbagrm.2021.194746
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发表时间：
2021-08-26
影响因子：
4.7
通讯作者：
Nishida, Kensei
中科院分区：
文献类型：
--
作者：
Nishikawa, Tatsuya;Kuwano, Yuki;Nishida, Kensei
核纤层蛋白A/C蛋白是核纤层的主要成分，由LMNA基因编码。这些蛋白质具有多种细胞功能，包括DNA转录和复制、染色质组织、细胞周期调节和细胞凋亡。LMNA中的突变与称为核纤层蛋白病的多种疾病相关。LMNA在癌症中具有意义;然而，其在癌细胞中失调的机制尚未完全了解。在这项研究中，在LMNA转录变体中，我们专注于转录变体6（称为LMNA-V6），其包含LMNA外显子1上游的独特3个外显子。LMNAV 6的启动子区形成多个G-四链体，并增加其转录活性。此外，LMNA-V6负调控其他LMNA mRNA变体，核纤层蛋白A和核纤层蛋白C，通过直接与其启动子的相互作用。LMNA-V6的敲低降低了结肠癌细胞的增殖，而LMNA-V6独特的3个外显子的过表达增加了细胞生长。此外，微阵列基因表达谱显示LMNA-V6水平的改变影响结肠癌细胞中p53的表达。综上所述，结果表明LMNA-V6可能是一种新的功能性RNA，其表达通过结肠癌细胞中的多个Gquadruplex进行调节。
Lamin A/C proteins, major components of the nuclear lamina, are encoded by the LMNA gene. These proteins have multiple cellular functions, including DNA transcription and replication, chromatin organization, regulation of the cell cycle, and apoptosis. Mutations in LMNA are associated with a variety of diseases called laminopathies. LMNA has implications in cancer; however, its mechanisms of dysregulation in cancer cells are not yet fully understood. In this study, among the LMNA transcript variants, we focused on a transcriptional variant 6 (termed LMNA-V6), which contains unique 3 exons upstream of exon 1 of LMNA. The promoter region of LMNAV6 formed multiple G-quadruplexes and increased its transcriptional activity. Moreover, LMNA-V6 negatively regulated other LMNA mRNA variants, lamin A and lamin C, via direct interaction with their promoter. Knockdown of LMNA-V6 decreased the proliferation of colon cancer cells, whereas overexpression of the unique 3 exons of LMNA-V6 increased cell growth. Furthermore, microarray gene expression profiling showed that alteration of LMNA-V6 levels influenced the expression of p53 in colon cancer cells. Taken together, the results suggest that LMNA-V6 may be a novel functional RNA whose expression is regulated through multiple Gquadruplexes in colon cancer cells.