# Role of the tRNA methyltransferase AlkBH8 in Colorectal Cancer

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $211,249

## Abstract

Project Summary:
Reactive Oxygen Species (ROS) are produced as byproducts of oxidative phosphorylation and are found
to be elevated in most cancers. In order to prevent ROS mediated cellular toxicity, cancer cells upregulate
production of ROS detoxifying enzymes such as Glutathione Peroxidase 4 (GPx4). Essential to the catalytic
activity of GPx4 is a catalytic selenocysteine residue, incorporated through specific reprogramming of the
UGA-STOP codon by tRNA-selenocysteine (tRNASec). tRNASec requires chemical modification of its
anticodon by the tRNA methyltransferase AlkBH8 for proper recognition and decoding ability of the UGA
codon. Our preliminary data indicate that high levels of AlkBH8 are correlated with worse prognostic
outcomes in colorectal cancer and that loss of AlkBH8 induces a growth arrest and reduces tumor
forming ability in several colorectal cancer cell lines. However, at present almost nothing is known
regarding the role of AlkBH8 and its tRNA modification in cancer cell growth and survival. Therefore, the
studies proposed here are intended to fill a critical void in our understanding of tRNA modifications in
cancer. First, we will use an inducible knockdown model of AlkBH8 to investigate the mechanisms following
loss of AlkBH8 that lead to growth arrest and investigate whether this mechanism is conserved in in-vivo
xenograft models. Second, we will utilize in-vitro analysis of recombinant AlkBH8 in order to deconvolute
the contributions of each of its domains on its catalytic activity. The information generated through these
studies will seek to establish a novel therapeutic target in one of the most frequently diagnosed and
deadliest cancers across the world.

## Key facts

- **NIH application ID:** 10789193
- **Project number:** 1R21CA286898-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Markos Koutmos
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,249
- **Award type:** 1
- **Project period:** 2024-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789193

## Citation

> US National Institutes of Health, RePORTER application 10789193, Role of the tRNA methyltransferase AlkBH8 in Colorectal Cancer (1R21CA286898-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10789193. Licensed CC0.

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