The biological process of lysine-tRNA charging is therapeutically targetable in liver cancer

Ruyi Zhang; Lisanne Noordam; Xumin Ou; Buyun Ma; Yunlong Li; Pronay Das; Shaojun Shi; Jiaye Liu; Ling Wang; Pengfei Li; Monique M A Verstegen; D Srinivasa Reddy; Luc J W van der Laan; Maikel P Peppelenbosch; Jaap Kwekkeboom; Ron Smits; Qiuwei Pan

doi:10.1111/liv.14692

The biological process of lysine-tRNA charging is therapeutically targetable in liver cancer

Liver Int. 2021 Jan;41(1):206-219. doi: 10.1111/liv.14692. Epub 2020 Oct 20.

Authors

Ruyi Zhang¹, Lisanne Noordam¹, Xumin Ou^{1

2}, Buyun Ma¹, Yunlong Li¹, Pronay Das³, Shaojun Shi⁴, Jiaye Liu¹, Ling Wang¹, Pengfei Li¹, Monique M A Verstegen⁴, D Srinivasa Reddy³, Luc J W van der Laan⁴, Maikel P Peppelenbosch¹, Jaap Kwekkeboom¹, Ron Smits¹, Qiuwei Pan¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
² Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
³ Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune, India.
⁴ Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Abstract

Background & aims: Mature transfer RNAs (tRNA) charged with amino acids decode mRNA to synthesize proteins. Dysregulation of translational machineries has a fundamental impact on cancer biology. This study aims to map the tRNAome landscape in liver cancer patients and to explore potential therapeutic targets at the interface of charging amino acid with tRNA.

Methods: Resected tumour and paired tumour-free (TFL) tissues from hepatocellular carcinoma (HCC) patients (n = 69), and healthy liver tissues from organ transplant donors (n = 21), HCC cell lines, and cholangiocarcinoma (CC) patient-derived tumour organoids were used.

Results: The expression levels of different mature tRNAs were highly correlated and closely clustered within individual tissues, suggesting that different members of the tRNAome function cooperatively in protein translation. Interestingly, high expression of tRNA-Lys-CUU in HCC tumours was associated with more tumour recurrence (HR 1.1; P = .022) and worse patient survival (HR 1.1; P = .0037). The expression of Lysyl-tRNA Synthetase (KARS), the enzyme catalysing the charge of lysine to tRNA-Lys-CUU, was significantly upregulated in HCC tumour tissues compared to tumour-free liver tissues. In HCC cell lines, lysine deprivation, KARS knockdown or treatment with the KARS inhibitor cladosporin effectively inhibited overall cell growth, single cell-based colony formation and cell migration. This was mechanistically mediated by cell cycling arrest and induction of apoptosis. Finally, these inhibitory effects were confirmed in 3D cultured patient-derived CC organoids.

Conclusions: The biological process of charging tRNA-Lys-CUU with lysine sustains liver cancer cell growth and migration, and is clinically relevant in HCC patients. This process can be therapeutically targeted and represents an unexplored territory for developing novel treatment strategies against liver cancer.

Keywords: Lysyl-tRNA Synthetase; cladosporin; liver cancer; lysine; tRNA-Lys-CUU; tRNAome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Phenomena*
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Lysine
Neoplasm Recurrence, Local
Transfer RNA Aminoacylation

Substances

Lysine