LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis
Zechang Xin,
Chenyu Hu,
Chunfeng Zhang,
Ming Liu,
Juan Li,
Xiaoyan Sun,
Yang Hu,
Xiaofeng Liu,
Kun Wang
Affiliations
Zechang Xin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Chenyu Hu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Chunfeng Zhang
Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
Ming Liu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Juan Li
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Xiaoyan Sun
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Yang Hu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China
Xiaofeng Liu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Corresponding author.
Kun Wang
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Corresponding author.
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.
