HKDC1 reprograms lipid metabolism to enhance gastric cancer metastasis and cisplatin resistance via forming a ribonucleoprotein complex.

Autor: Zhao P; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Yuan F; Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China., Xu L; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Jin Z; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Liu Y; Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China., Su J; Department of Gastroenterology, Xuzhou Central Hospital, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, 221009, China., Yuan L; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Peng L; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Wang C; Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China. Electronic address: wangchaofu@126.com., Zhang G; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. Electronic address: guoxinz@njmu.edu.cn.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2023 Aug 10; Vol. 569, pp. 216305. Date of Electronic Publication: 2023 Jul 07.
DOI: 10.1016/j.canlet.2023.216305
Abstrakt: As essential modulators of transcription and translation, RNA-binding proteins (RBPs) are frequently dysregulated in cancer. Bioinformatics study reveals that the RNA-binding protein hexokinase domain component 1 (HKDC1) is overexpressed in gastric cancer (GC). As HKDC1 plays a role in lipid homeostasis in the liver and glucose metabolism in certain cancers, the exact mechanism of action of HKDC1 in GC remains largely unknown. Upregulation of HKDC1 correlates with chemoresistance and poor prognosis in GC patients. HKDC1 enhances invasion, migration and resistance to cisplatin (CDDP) in GC cells in vitro and in vivo. Comprehensive transcriptomic sequencing and metabolomic analysis reveal that HKDC1 mediates abnormal lipid metabolism in GC cells. Herein, we identify a number of HKDC1-binding endogenous RNAs in GC cells, including protein kinase, DNA-activated, catalytic subunit (PRKDC) mRNA. We further validate that PRKDC is a crucial downstream effector of HKDC1 induced-GC tumorigenesis depends on lipid metabolism. Interestingly, G3BP1, a well-known oncoprotein, can be bound by HKDC1. HKDC1 cooperates with G3BP1 to enhance the stability of PRKDC transcript. Our results reveal a novel HKDC1/G3BP1-PRKDC regulatory axis that induces GC metastasis and chemoresistance via reprogramming lipid metabolism, which may provide an effective therapeutic strategy for a subset of GC with HKDC1 overexpression.
Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interests.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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