# Role of KAT5 in lung cancer

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $417,904

## Abstract

PROJECT SUMMARY/ABSTRACT
 Lung cancer is the leading cause of cancer-related mortality in the United States. The overall 5-year
survival of patients diagnosed with lung cancer is 18%, and outcomes for advanced stage patients treated with
standard chemotherapies have plateaued. Recent discoveries of genetic alterations in receptor tyrosine
kinases such as Epidermal Growth Factor Receptor (EGFR) have led to development of tyrosine kinase
inhibitors as lung cancer therapies. However, intrinsic and acquired resistance to inhibitors is currently a major
problem in the clinic, making development of novel therapies for lung cancer imperative. Histone modifications,
including lysine acetylation, play crucial roles in transcriptional activation and elongation, gene silencing and
epigenetic cellular memory, and aberrant epigenetic changes are associated with oncogenesis. Among
epigenetic modifiers, aberrant activity of several lysine (K) acetyltransferases (KATs) is implicated in cancer
development. To assess the function of one of those acetyltransferases (KAT5) in lung cancer, we generated
conditional Kat5 knockout mice and found that lung-specific Kat5 deletion suppressed tumor formation induced
by EGFR-L858R-T790M. We also showed that mutant EGFR bound to and tyrosine-phosphorylated KAT5 at
two tyrosine residues in the catalytic domain, increasing its acetyltransferase activity. Thus, we hypothesize
that KAT5 is required for lung tumorigenesis induced by oncogenic kinases such as EGFR mutants. In Aim 1,
we will investigate how KAT5 tyrosine phosphorylation increases its acetylase activity and whether oncogenic
kinases such as mutant EGFR induce KAT5 activation in lung cancer. In Aim 2, we will investigate whether
KAT5 regulates Wnt/β-catenin signaling, which is crucial for lung tumorigenesis by activating EGFR mutations.
In addition, we will identify KAT5 effectors potentially responsible for tumorigenesis using biochemical analysis
plus a combination of RNA sequencing and chromatin immunoprecipitation sequencing. In Aim 3, we will ask
whether KAT5 is required for tumor initiation, maintenance of established lung tumors, or both, using
transgenic mouse models. Aim 3 also addresses a potential function for KAT5 in proliferation and self-renewal
in lung cancer stem/initiating cells. Experiments proposed here should lead to development of novel epigenetic
therapies and significantly impact care of patients with lung cancer, particularly those with unfavorable
prognosis, in the near future.

## Key facts

- **NIH application ID:** 9964262
- **Project number:** 1R01CA240257-01A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Susumu Kobayashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,904
- **Award type:** 1
- **Project period:** 2020-02-07 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964262

## Citation

> US National Institutes of Health, RePORTER application 9964262, Role of KAT5 in lung cancer (1R01CA240257-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9964262. Licensed CC0.

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