Inhibition of ribosomal RNA processing 15 Homolog (RRP15), which is overexpressed in hepatocellular carcinoma, suppresses tumour growth via induction of senescence and apoptosis.

Abstract

Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment.

• Authors: Dian Zhao, Liping Qian, Duanming Zhuang, Lei Wang, Yu Cao, Fan Zhou, Shu Zhang, Ying Liu, Ying Liang, Wenjie Zhang, Wei Kang, Ming Zhang, Yi Wang, Feng Zhang, Wei Zhang, Jiangqiang Xiao, Guifang Xu, Ying Lv, Xiaoping Zou, Yuzheng Zhuge, Bin Zhang
• Journal: Cancer letters (Cancer Lett) Vol. 519 Pg. 315-327 (10 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34343634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• RNA, Ribosomal
• RRP15 protein, human
• Ribosomal Proteins
• Tumor Suppressor Protein p53
• Hexokinase
• Phosphoric Monoester Hydrolases

Topics

• Apoptosis (genetics)
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (genetics, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Cellular Senescence (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Hep G2 Cells
• Hexokinase (genetics)
• Humans
• Liver Neoplasms (genetics, pathology)
• Neoplasm Recurrence, Local (genetics, pathology)
• Phosphoric Monoester Hydrolases (genetics)
• RNA, Ribosomal (genetics)
• Ribosomal Proteins (genetics)
• Signal Transduction (genetics)
• Tumor Suppressor Protein p53 (genetics)