Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, PR China.
Department of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, PR China.
Cell Death Dis. 2021 Mar 4;12(3):245. doi: 10.1038/s41419-021-03523-z.
The long noncoding RNA, LINC00518, is highly expressed in various types of cancers and is involved in cancer progression. Although LINC00518 promotes the metastasis of cutaneous malignant melanoma (CMM), the mechanism underlaying its effects on CMM radiosensitivity remains unclear. In this study, LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which increased sensitivity to radiotherapy via inhibition of the hypoxia-inducible factor 1α (HIF-1α)/lactate dehydrogenase A glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase 2, which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signaling with initially activated glycolysis and radioresistance in CMM cells was impaired by Santacruzamate A, a histone deacetylase inhibitor, and 2-deoxy-D-glucose, a glycolytic inhibitor. Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumor model. In conclusion, LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our study, may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.
长链非编码 RNA LINC00518 在多种类型的癌症中高度表达，并参与癌症的进展。尽管 LINC00518 促进了皮肤恶性黑色素瘤（CMM）的转移，但它对 CMM 放射敏感性的影响机制尚不清楚。在本研究中，LINC00518 在 CMM 样本中表达显著上调，且 LINC00518 水平与 CMM 患者的预后不良相关。在 CMM 细胞中敲低 LINC00518 显著抑制细胞侵袭、迁移、增殖和集落形成。LINC00518 介导的侵袭、迁移、增殖和集落形成在体外受到 microRNA miR-33a-3p 的负调控，通过抑制缺氧诱导因子 1α（HIF-1α）/乳酸脱氢酶 A 糖酵解轴增加了对放疗的敏感性。此外，HIF-1α 识别 miR-33a-3p 启动子区域并募集组蛋白去乙酰化酶 2，从而降低 miR-33a-3p 的表达并形成 LINC00518/miR-33a-3p/HIF-1α 负反馈环。此外，Santacruzamate A（一种组蛋白去乙酰化酶抑制剂）和 2-脱氧-D-葡萄糖（一种糖酵解抑制剂）抑制 CMM 细胞中最初激活的糖酵解和放射抵抗信号。最后，敲低 LINC00518 表达可在体内皮下植入肿瘤模型中增强 CMM 癌细胞对放疗的敏感性。总之，LINC00518 被证实是 CMM 的致癌基因，通过 miR-33a-3p/HIF-1α 负反馈环调节糖酵解诱导放射抵抗。我们的研究可能为改善 CMM 放疗的治疗效果提供了一种潜在策略。
