Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of β-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC.

中文翻译：

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LncRNA-HMG 通过抑制 p53 介导的铁死亡诱导结直肠癌细胞产生化疗耐药性


化疗后，过量的活性氧 （ROS） 通常会导致癌细胞产生大量脂质过氧化物并诱导细胞死亡，即铁死亡。ROS 的消除是肿瘤细胞逃离铁死亡并获得耐药性的关键。然而，长链非编码 RNA （lncRNA） 在 ROS 代谢和肿瘤耐药性中的确切功能仍然难以捉摸。在这项研究中，我们通过高通量筛选将 LncRNA-HMG 鉴定为结直肠癌 （CRC） 中化疗耐药相关的 lncRNA。LncRNA-HMG 的异常高表达预示着 CRC 患者的预后较差。同时，我们发现 LncRNA-HMG 保护 CRC 细胞在化疗时免受铁死亡，从而增强 CRC 细胞的耐药性。LncRNA-HMG 与 p53 结合并促进 MDM2 介导的 p53 降解。p53 降低诱导 SLC7A11 和 VKORC1L1 的上调，这有助于增加还原剂的供应并消除过量的 ROS。因此，CRC 细胞从铁死亡中逃脱并获得化疗耐药性。重要的是，在患者来源的异种移植物 （PDX） 模型中，反义寡核苷酸 （ASO） 对 LncRNA-HMG 的抑制使 CRC 细胞对化疗显着敏感。LncRNA-HMG 也是 β-catenin/TCF 的转录靶标，激活的 Wnt 信号触发 LncRNA-HMG 的显着上调。总的来说，这些发现表明 LncRNA-HMG 促进 CRC 化疗耐药，可能是 CRC 的预后或治疗靶点。