A novel regulatory role of leucyl-tRNA synthetase in supporting human cancer growth

Human cytoplasmic leucyl-tRNA synthetase (LARS) is known to catalyze the ligation of leucine to tRNALeu during protein biosynthesis. Emerging data indicate that LARS also acts as a nutrient sensor in a non-canonical function to regulate cell growth. However, whether LARS is involved in cancer cell growth and tumor development remains unknown. In my first project, I determined that LARS is expressed at high levels in human liver cancer. Moreover, its increased expression correlates with poor clinical outcomes in liver cancer patients. Knocking down LARS in HepG2 liver cancer cells suppressed both 2D and 3D cell proliferation and growth, yet promoted cell migration, without affecting global protein translation. RNA sequencing data revealed that the differentially expressed genes in response to LARS knockdown were significantly clustered in cellular senescence pathway. This is further confirmed by the observations of elevated p21 and p16 expressions, increased senescence-associated β-galactosidase activity, as well as cell cycle arrest in LARS knockdown HepG2 cells, which are all well-known markers of senescent cells. In addition, depletion of LARS triggered autophagy by increasing autophagic flux. Cellular stress with increased production of reactive oxygen species and decreased mitochondria membrane potential was also induced in LARS knockdown HepG2 cells. These findings suggest that LARS regulates liver cancer cell proliferation via multiple cellular responses and LARS may serve as a promising therapeutic target for future liver cancer treatment. In my second project, I also identified a potential tumorigenic function of LARS in human breast cancer. The protein levels of LARS are upregulated in breast tumor tissues. In addition, LARS knockdown specifically suppressed estrogen receptor alpha (ERα)-positive breast cancer cells proliferation and migration, while had no significant influence on ERα-negative breast cancer cells. Without a remarkable impact on global protein synthesis, LARS knockdown inhibited ERα expression by enhancing protein degradation. As ERα is a leucin rich protein by analyzing its amino acid composition, we therefore hypothesize that LARS may support ERα-positive breast tumor development by regulating ERα protein stability as well as specifically improving translation of ERα in the leucin-codon dependent manner.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Lin, Xiaodan

Contributors dc:contributor

• Martinis, Susan A
• Chen, Lin-Feng
• Nelson, Erik R
• Zhang, Kai

• Leucyl-trna Synthetase
• Liver Cancer
• Cellular Senescence
• Autophagy
• Cellular Stress

Statement dc:rights

• Copyright 2024 Xiaodan Lin

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/127467

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F127467