To fill this knowledge gap, a group of researchers led by Professor Kangseok Lee, from the Department of Life Science, Chung-Ang University set out to explore the biogenesis and function of specific tRFs like tRHs. Their study published in Volume 15 of Nature Communications on 28 October 2024, opens exciting avenues for the future of cancer therapies and introduces potential biomarkers for improved clinical outcomes.
This study was inspired by a serendipitous discovery in 2010, when the researchers found high levels of small RNA fragments derived from specific tRNAs, rather than the anticipated microRNAs in ovarian cancer samples. "At that time, the physiological roles of tRNA fragments were unknown. We felt compelled to investigate further to understand the role of these fragments in cancer," shares Prof. Kangseok Lee.
To investigate the role of a specific underexplored fragment, 5′-tRH-GlyGCC in cancer, the researchers employed a combination of cutting-edge molecular and biochemical techniques. Nanopore sequencing was used to analyze the transcriptome, while alternative splicing assays were performed to assess how the RNA fragment affected gene expression. Additionally, the interaction between 5′-tRH-GlyGCC and heterogeneous nuclear ribonucleoprotein (HNRNP) proteins, involved in splicing, was closely examined. Furthermore, the researchers conducted in vitro experiments to analyze cancer cell proliferation, and used in vivo xenograft mouse models to evaluate the therapeutic potential of targeting 5′-tRH-GlyGCC.
The researchers found that under endoplasmic reticulum stress, inositol-requiring enzyme 1α (IRE1α) splits tRNAGly(GCC) to produce 5′-tRH-GlyGCC. Furthermore, the results revealed that 5′-tRH-GlyGCC plays a critical role in alternative splicing and messenger RNA isoform regulation, influencing the expression of genes involved in cancer progression. The study also found that this RNA fragment interacts with HNRNP proteins, which regulate splicing. In vitro experiments showed that modulating the levels of 5′-tRH-GlyGCC can significantly affect cancer cell proliferation. “Our study addresses a long-standing question in RNA and cancer biology. We have uncovered how specific tRNA fragments are produced and their critical roles in cellular stress and cancer, which opens novel opportunities for diagnostic and therapeutic applications,” explains Prof. Lee
In xenograft mouse models, suppressing this RNA fragment using antisense oligonucleotides (ASOs) led to tumor regression. These findings suggest that 5′-tRH-GlyGCC could serve as a biomarker for early-stage cancer detection, as its level can be easily detected in blood samples using RT-PCR, similar to coronavirus detection. Moreover, its role in tumor growth makes it a promising target for therapeutic interventions. Prof. Lee explains, "Blocking these tRNA fragments led to tumor regression in mouse models. We are now exploring how to deliver ASOs into human cells, bringing us closer to clinical applications."
We hope this study paves the way for innovative approaches in precision medicine, leading to more effective diagnostics and personalized cancer therapies.
***
Reference
Authors: Hanyong Jin¹, Ji-Hyun Yeom², ³, Eunkyoung Shin², ⁴, Yoonjie Ha², Haifeng Liu⁵, Daeyoung Kim², Minju Joo², ³, Yong-Hak Kim⁴, Hak Kyun Kim², Minkyung Ryu², ³, Hong-Man Kim³, Jeongkyu Kim², Keun P. Kim², Yoonsoo Hahn², Jeehyeon Bae⁵ and Kangseok Lee², ³
Title of original paper: 5′-tRNAGly (GCC) halves generated by IRE1α are linked to the ER stress response
Journal: Nature Communications
DOI: 10.1038/s41467-024-53624-4
Affiliation:
1Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, China.
2Department of Life Science, Chung-Ang University, Republic of Korea.
3R & D Institute, NES Biotechnology, Republic of Korea.
4Department of Microbiology, School of Medicine, Catholic University of Daegu, Republic of Korea.
5School of Pharmacy, Chung-Ang University, Republic of Korea.
Corresponding author’s email:
jeehyeon@cau.ac.kr, kangseok@cau.ac.kr
About Chung-Ang University
Chung-Ang University is a private comprehensive research university located in Seoul, South Korea. It was started as a kindergarten in 1916 and attained university status in 1953. It is fully accredited by the Ministry of Education of Korea. Chung-Ang University conducts research activities under the slogan of “Justice and Truth.” Its new vision for completing 100 years is “The Global Creative Leader.” Chung-Ang University offers undergraduate, postgraduate, and doctoral programs, which encompass a law school, management program, and medical school; it has 16 undergraduate and graduate schools each. Chung-Ang University’s culture and arts programs are considered the best in Korea.
Website: https://neweng.cau.ac.kr/index.do
About the authors
Drs. Kangseok Lee and Jeehyeon Bae hold the position of professor at Chung-Ang University and are co-founders of NES Biotechnology. Drs. Eunkyoung Shin and Hanyoung Jin, who joined this study as postdoctoral fellows, moved on to faculty positions in other universities where they continued to work on finishing this study. Drs. Ji-Hyun Yeom, Hong-Man Kim, Minju Joo, and Minkyung Ryu also worked on this study as postdoctoral fellows and contributed to development of nucleic acid delivery system in NES biotechnology where they took positions in R & D section. Dr. Daeyoung Kim obtained PhD based on his contribution to the first part of this study and currently works at CJ group. Dr. Haifeng Liu performed experiments that are related to the physiological function of tRNA fragments to address comments raised during the final two rounds of revision.
Dr. Kangseok Lee: https://scholarworks.bwise.kr/cau/researcher-profile?ep=514
Dr. Jeehyeon Bae: https://scholarworks.bwise.kr/cau/researcher-profile?ep=874
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