Ling Xiaodong, Qi Cuicui, Cao Kui, Lu Mengdi, Yang Yingnan, Zhang Jinfeng, Zhang Luquan, Zhu Jinhong, Ma Jianqun
Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China.
Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China.
Cell Death Discov. 2024 Apr 30;10(1):203. doi: 10.1038/s41420-024-01965-w.
We previously reported lncRNA HAR1A as a tumor suppressor in non-small cell lung cancer (NSCLC). However, the delicate working mechanisms of this lncRNA remain obscure. Herein, we demonstrated that the ectopic expression of HAR1A inhibited the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of NSCLC cells and enhanced paclitaxel (PTX) sensitivity in vitro and in vivo. We identified the oncogenic protein annexin 2 (ANXA2) as a potential interacting patterner of HAR1A. HAR1A overexpression enhanced ANXA2 ubiquitination and accelerated its degradation via the ubiquitin-proteasome pathway. We further uncovered that HAR1A promoted the interaction between E3 ubiquitin ligase TRIM65 and ANXA2. Moreover, the ANXA2 plasmid transfection could reverse HAR1A overexpression-induced decreases in proliferation, migration, and invasion of NSCLC cells and the activity of the NF-κB signaling pathway. Finally, we found that HAR1A loss in NSCLC might be attributed to the upregulated METTL3. The mA modification levels of HAR1A were increased in cancer cells, while YTHDF2 was responsible for recognizing mA modification in the HAR1A, leading to the disintegration of this lncRNA. In conclusion, we found that METTL3-mediated mA modification decreased HAR1A in NSCLC. HAR1A deficiency, in turn, stimulated tumor growth and metastasis by activating the ANXA2/p65 axis.
我们之前报道lncRNA HAR1A在非小细胞肺癌（NSCLC）中作为一种肿瘤抑制因子。然而，这种lncRNA的精细作用机制仍不清楚。在此，我们证明了HAR1A的异位表达在体外和体内均抑制NSCLC细胞的增殖、上皮-间质转化（EMT）、迁移和侵袭，并增强了对紫杉醇（PTX）的敏感性。我们鉴定出致癌蛋白膜联蛋白2（ANXA2）是HAR1A潜在的相互作用蛋白。HAR1A过表达增强了ANXA2的泛素化，并通过泛素-蛋白酶体途径加速其降解。我们进一步发现HAR1A促进了E3泛素连接酶TRIM65与ANXA2之间的相互作用。此外，ANXA2质粒转染可逆转HAR1A过表达诱导的NSCLC细胞增殖、迁移和侵袭的减少以及NF-κB信号通路的活性。最后，我们发现NSCLC中HAR1A的缺失可能归因于METTL3的上调。癌细胞中HAR1A的m⁶A修饰水平增加，而YTHDF2负责识别HAR1A中的m⁶A修饰，导致这种lncRNA的降解。总之，我们发现METTL3介导的m⁶A修饰降低了NSCLC中的HAR1A。反过来，HAR1A的缺乏通过激活ANXA2/p65轴刺激肿瘤生长和转移。
