Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Department of Biochemistry and Molecular Biology, Medical School of Southeast University, Nanjing, China.
Department of Thoracic and Cardiovascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Oncogene. 2021 Jun;40(22):3870-3884. doi: 10.1038/s41388-021-01816-3. Epub 2021 May 10.
An increasing number of studies have shown that long-noncoding RNAs (lncRNAs) are involved in the post-translational modifications (PTMs) of protein in a variety of tumors. However, little is known about the exact regulation mechanism of lncRNAs in regulating PTMs in non-small-cell lung carcinoma (NSCLC) proliferation. Metastasis-associated lung adenocarcinoma transcript1 (MALAT1) and GINS complex subunit 1(GINS1) both were upregulated and promoted proliferation progression in NSCLC. In this study, the clinicopathologic significance of MALAT1 and GINS1 in NSCLC was investigated, a positive correlation in their expression was found. The silencing of MALAT1 decreased GINS1 expression and inhibited NSCLC proliferation in vitro and in vivo. The upregulation of GINS1 reversed NSCLC proliferation inhibited by MALAT1 knockdown. FOXP3 (forkhead box protein 3) was identified as the critical transcription factor for GINS1 transcription. In addition, MALAT1 could stabilize FOXP3 by binding to zinc finger (ZF) domain and leucine zipper (LZ) domain of FOXP3. Interestingly, these two domains were also interaction domains for FOXP3 binding with E3 ligase STUB1 (STIP1 homology and U-box containing protein 1). In this way, MALAT1 masked the protein-interacting domain, and inhibited FOXP3 ubiquitination by STUB1. Together, our results identified a novel regulatory axis of MALAT1-FOXP3-GINS1, and demonstrated that MALAT1 played an important modulatory role in PTM of FOXP3 which affects GINS1 transcription and drives proliferation character in NSCLC.
越来越多的研究表明，长非编码 RNA（lncRNA）参与多种肿瘤中蛋白质的翻译后修饰（PTMs）。然而，lncRNA 调节非小细胞肺癌（NSCLC）增殖中 PTM 的确切调节机制知之甚少。转移相关肺腺癌转录物 1（MALAT1）和 GINS 复合物亚基 1（GINS1）在 NSCLC 中均上调并促进增殖进展。在本研究中，研究了 MALAT1 和 GINS1 在 NSCLC 中的临床病理意义，发现它们的表达呈正相关。沉默 MALAT1 降低了 GINS1 的表达，并抑制了 NSCLC 的体外和体内增殖。上调 GINS1 逆转了 MALAT1 敲低抑制的 NSCLC 增殖。FOXP3（叉头框蛋白 3）被鉴定为 GINS1 转录的关键转录因子。此外，MALAT1 可以通过与 FOXP3 的锌指（ZF）结构域和亮氨酸拉链（LZ）结构域结合来稳定 FOXP3。有趣的是，这两个结构域也是 FOXP3 与 E3 连接酶 STUB1（STIP1 同源和 U -box 包含蛋白 1）结合的相互作用结构域。通过这种方式，MALAT1 掩盖了蛋白质相互作用域，并抑制了 STUB1 对 FOXP3 的泛素化。总之，我们的研究结果确定了 MALAT1-FOXP3-GINS1 的新调节轴，并表明 MALAT1 在 FOXP3 的 PTM 中发挥重要的调节作用，影响 GINS1 的转录并驱动 NSCLC 的增殖特征。
