xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade

• Published in: Cell death & disease 2022-04, Vol.13 (4), p.373-15, Article 373
• Main Authors: Tang, Bufu, Zhu, Jinyu, Liu, Fangming, Ding, Jiayi, Wang, Yajie, Fang, Shiji, zheng, Liyun, Qiu, Rongfang, Chen, Minjiang, Shu, Gaofeng, Xu, Min, Lu, Chenying, Zhao, Zhongwei, Yang, Yang, Ji, Jiansong
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/31; 13/51; 45/77; 631/67/395; 692/699/67/1857; 692/699/67/71; AKT protein; Amino Acid Transport System y+ - metabolism; Antibodies; Antitumor activity; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; Humans; Immunofluorescence; Immunology; Life Sciences; Metastases; Oncogenes; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Therapeutic targets; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumorigenesis; Up-regulation; Up-Regulation - genetics; Western blotting
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04827-4

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignant tumors globally, and its occurrence and progression are closely related to the poor histological features and complex molecular characteristics among patients. It is urgent to identify specific biomarkers for effective treatment of CRC. In this study, we performed comprehensive experiments to validate the role of xCT expression in CRC tumorigenesis and stemness and confirmed xCT knockdown significantly suppressed the proliferation, migration, and stemness of CRC cells in vitro and effectively inhibited CRC tumorigenesis and metastasis in vivo. In addition, bioinformatic analysis and luciferase assays were used to identify E2F1 as a critical upstream transcription factor of SLC7A11 (the gene encoding for xCT) that facilitated CRC progression and cell stemness. Subsequent RNA sequencing, western blotting, rescue assay, and immunofluorescence assays revealed MELK directly co-expressed with xCT in CRC cells, and its upregulation significantly attenuated E2F1/xCT-mediated tumorigenesis and stemness in CRC. Further molecular mechanism exploration confirmed that xCT knockdown may exert an antitumor effect by controlling the activation of MELK-mediated Akt/mTOR signaling. Erastin, a specific inhibitor of xCT, was also proven to effectively inhibit CRC tumorigenesis and cell stemness. Altogether, our study showed that E2F1/xCT is a promising therapeutic target of CRC that promotes tumorigenesis and cell stemness. Erastin is also an effective antitumoral agent for CRC.