RNA fragment is key regulator of gene expression and potential therapeutic target in cancer, study reveals microbiologystudy

A novel study from Korea uncovers the process of synthesis and pivotal role of the transfer RNA-derived fragment, 5′-tRH-Gly^GCC, in cancer progression. By interacting with splicing factors, it regulates gene expression, alternative splicing, and messenger RNA processing.

Transfer RNA-derived fragments (tRFs) are small molecules present in most organisms. tRHs or tRNA halves are generated when certain tRFs are split at specific sites by enzymes. Although tRFs carry out various biological functions, not much is known about their synthesis.

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 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,” said Prof. Kangseok Lee.

To investigate the role of a specific underexplored fragment, 5′-tRH-Gly^GCC 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-Gly^GCC 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-Gly^GCC.

The researchers found that under endoplasmic reticulum stress, inositol-requiring enzyme 1α (IRE1α) splits tRNA^Gly(GCC) to produce 5′-tRH-Gly^GCC. Furthermore, the results revealed that 5′-tRH-Gly^GCC 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-Gly^GCC 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-Gly^GCC 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.”

This research highlights the role of 5′-tRH-Gly^GCC as a cancer biomarker and explores its potential as a therapeutic target. With promising results from antisense oligonucleotide therapies, this discovery could pave the way for groundbreaking advancements in cancer treatment.

Provided by
Chung Ang University