# Role of the METTL13 Lysine Methyltransferase in Signaling and Cancer

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $485,495

## Abstract

ABSTRACT
 Our overarching goal is to better understand the role of post-translational modifications (PTMs) of cellular
proteins in cancer with the underlying assumption that the enzymes that catalyze the addition or the removal of
these PTMs are candidate therapeutic targets in cancer. While enzymes such as protein kinases have been
extensively studied in cancer, new classes of enzymes have recently emerged as potential cancer targets. In
particular, more than 100 lysine methyltransferases (KMTs) are predicted to be present in the human proteome
and many are implicated in cancer etiology. However, the catalytic activity and substrate specificity for many of
these enzymes remains unknown. In particular, functions for the vast majority of the large family of seven β-
strand KMTs are not known. A central hypothesis to be tested here is that uncovering the activities of these
orphan KMTs may provide new links between protein lysine methylation signaling and cancer biology.
 Here we focus on the candidate KMT METTL13 (Methyltransferase-like protein 13) as a potential critical
regulator of tumorigenesis. The METTL13 gene is amplified in many cancers and METTL13 mRNA is over-
expressed in diverse tumor types, including several were METTL13 expression negatively correlates with
patient survival. However, METTL13 is an orphan enzyme and knowledge of any potential substrates and the
overall mode of action of this protein in cells and in vivo is obscure. Based on preliminary observations, we
hypothesize that METTL13 up-regulates protein translation to promote tumorigenesis.
 In Aim 1 we characterize the physiologic catalytic activity of METTL13 and the molecular functions of
METTL13 in the regulation of eEF1A activity in vitro and in protein synthesis in cells. We will also investigate
METTL13 and methylated eEF1A interacting partners and how these pathways intersect to influence cancer
cell phenotypes. The goal of Aim 2 is to elucidate the role of METTL13 in tumors driven by oncogenic KRAS.
We will test the hypothesis that METTL13, via its methylation activity, cooperates with KRAS signaling to
promote the unlimited expansion of cancer cells in vivo using mouse models of pancreatic ductal
adenocarcinoma and lung adenocarcinoma, in which the RAS pathway is frequently activated. We will also
investigate the tumorigenic role of METTL13 in human tissue using patient-derived xenograft (PDX) models.
We will assess the effects of METTL13 loss on protein translation in vivo. Finally, we will explore potential
synergies of METTL13 ablation in combination with inhibitors of cell survival and growth pathways in pre-
clinical models of pancreatic and lung cancers.

## Key facts

- **NIH application ID:** 9878807
- **Project number:** 5R01CA236118-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Or P. Gozani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,495
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878807

## Citation

> US National Institutes of Health, RePORTER application 9878807, Role of the METTL13 Lysine Methyltransferase in Signaling and Cancer (5R01CA236118-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9878807. Licensed CC0.

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