Original ResearchFull Report: GI CancerNucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis
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Reagents and Treatments
Cells starved for 24 hours were supplemented with serum-free medium containing recombinant human insulin-like growth factor 1 (IGFI; 20 ng/mL; R&D System) or insulin (200 nmol/L; HY-P0035, MedChemExpress) for 3 hours and then were analyzed for protein or messenger (m)RNA expression. To block, mechanistic target of rapamycin complex 1 (mTORC1) signaling or SP1, cells were incubated with rapamycin (10 nmol/L; Cell Signaling Technology) or tolfenamic acid (15 μg/mL; Selleck) for 24 hours. To block
HEAT Repeat Containing 1 Is Up-regulated in Hepatocellular Carcinoma and Correlates With Hepatocellular Carcinoma Progression and Prognosis
Given the importance of ribosome biogenesis in HCC carcinogenesis,5,25 we vertically compared the expression profiles of 307 ribosome biogenesis-related genes (Gene Ontology [GO]: 0042254) (Supplementary Table 4) in the Gene Expression Omnibus Series (GSE) 14520 data set (the largest data set, containing 247 HCC samples and 242 normal tissues). We found that HEATR1 was the most overexpressed gene with the lowest P value (fold change = 2.837, false discovery rate–adjusted P = 7.46E−85); its
Discussion
Ribosome biogenesis, which is regulated by growth signaling that converges in the nucleolus, has been revealed as a druggable pathway for cancer therapeutics.9,44 In this study, we found that HEATR1 is up-regulated in HCC via the IGF1–mTORC1–SP1 axis and contributes to HCC growth by promoting ribosome biogenesis. Disruption of HEATR1 impaired ribosome biogenesis and global protein synthesis, leading to decreased cytoplasmic proteasome activity and IκB/NF-κB signaling. Simultaneously, nucleolar
Acknowledgments
Xiao-Mei Yang, Xiao-Qi Wang, and Li-Peng Hu contributed equally to this article. The authors thank Xiao Li, Shan Zhang, Hui-Ling Wang, Jun-Ping Ao, and Juan Yang for their technical support.
CRediT Authorship Contributions
Zhi-Gang Zhang, PhD (Conceptualization: Lead; Data curation: Lead; Funding acquisition: Lead; Project administration: Lead; Supervision: Lead; Writing – review & editing: Lead).
Xiao-Mei Yang, PhD (Conceptualization: Lead; Data curation: Lead; Funding acquisition: Equal; Investigation: Lead; Methodology:
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Conflicts of interest The authors disclose no conflicts.
Funding This study was supported by the National Natural Science Foundation of China (82230087 to Zhi-Gang Zhang and 81972582 to Xiao-Mei Yang), the Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University (YG2021ZD08 to Zhi-Gang Zhang), the Shanghai Pilot Program for Basic Research—Shanghai Jiao Tong University (21TQ1400225 to Shu-Heng Jiang), the Natural Science Foundation of Shanghai (22ZR1460000 to Xue-Li Zhang, 21ZR1461300 to Li-Peng Hu), the Shanghai Municipal Health Commission (No. 202040092 to Xue-Li Zhang), Shanghai Sailing Program (21YF1445200 to Li-Peng Hu), and the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20210802).
Author names in bold designate shared co-first authorship.