State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive Disease; Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Middle Shandong Road, 200001, Shanghai, China.
Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, College of Fishery and Life Science, Shanghai Ocean University, Shanghai, 201306, China.
Signal Transduct Target Ther. 2021 Feb 19;6(1):70. doi: 10.1038/s41392-020-00446-7.
Long non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
长链非编码 RNA（lncRNAs）在结直肠癌的发生发展中起着关键作用。在这里，我们旨在鉴定风险 SNP 诱导的 lncRNAs，并研究它们在结直肠癌发生发展中的作用。首先，我们确定 1q41 位点上的 rs6695584 是致病 SNP。rs6695584 的 A>G 突变创造了 BATF 的蛋白结合基序，改变了增强子活性，随后激活了 lncSLCC1 的表达。在两个独立的 CRC 队列中的进一步验证证实了 lncSLCC1 在 CRC 组织中的上调，并表明 lncSLCC1 表达的增加与 CRC 患者的不良预后相关。在机制上，lncRNA-SLCC1 与 AHR 相互作用，并转录激活 HK2 的表达，HK2 是葡萄糖代谢中的关键酶，从而驱动糖酵解途径并加速 CRC 肿瘤的生长。功能测定表明，lncSLCC1 通过 HK2 在 CRC 中诱导糖酵解激活和肿瘤生长。此外，HK2 在结直肠癌组织中上调，并与 lncSLCC1 的表达和患者的生存呈正相关。总之，我们的研究结果揭示了一种风险 SNP 介导的致癌基因 lncRNA-SLCC1 通过激活糖酵解途径促进 CRC 的发生发展。
