# Novel arginine-methylation mediated regulation of YAP1 in K-Ras mutant lung adenocarcinomas

> **NIH NIH R03** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $164,700

## Abstract

Lung cancer is the leading cause of cancer-related death in the United States, with a majority, around 85%
resulting from non-small cell lung cancer (NSCLC). The overall survival rate for NSCLC is low, due to poor
response to targeted therapy and the development of resistance. While immunotherapy is beneficial for about
30% of patients that harbor mutations in the KRAS oncogene, however, does not benefit the vast majority of
the patients. In this context, studies showed that the transcriptional co-activator protein, YAP1, a downstream
mediator of the Hippo signaling pathway, plays a major role in the stemness, growth, and metastasis of
NSCLCs. In the present study, we find that a non-canonical I kinase, TBK1 (Tank-binding Kinase 1) can
physically interact and phosphorylate YAP1. Depletion or inhibition of TBK1 significantly elevated the levels of
the YAP1 protein, selectively in KRAS mutant lung cancer cells. This occurred through enhanced methylation
of YAP1 on arginine residues. TBK1 is known to play an important role in innate immunity but its oncogenic
role, especially in the field of lung cancer, is not fully elucidated. Our proposed project will investigate the
functional importance of this novel arginine-methylation of YAP1 protein by certain protein arginine-methyl
transferases (PRMTs), especially PRMT4/CARM1 and PRMT5. Inhibition of these PRMTs by a pan-PRMT
inhibitor significantly downregulated the levels of YAP1 even in the TBK1 depleted condition. These novel
findings raise the possibility that inhibiting TBK1 and PRMTs simultaneously might be a viable strategy to
combat NSCLCs, and we will examine this in a series of in-depth in vitro and in vivo studies. The Specific Aims
which will be covered are: (1) To understand the differential regulation of YAP1 by TBK1 in KRAS versus
EGFR mutant lung adenocarcinoma and (2) To study the novel methylation status of YAP1 molecule under
TBK1 depletion in KRAS mutant background leading to YAP1 protein stability.

## Key facts

- **NIH application ID:** 10046443
- **Project number:** 1R03CA246027-01A1
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Biswarup Saha
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,700
- **Award type:** 1
- **Project period:** 2020-07-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046443

## Citation

> US National Institutes of Health, RePORTER application 10046443, Novel arginine-methylation mediated regulation of YAP1 in K-Ras mutant lung adenocarcinomas (1R03CA246027-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10046443. Licensed CC0.

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