# Control of mutant p53 stability via the mevalonate pathway-DNAJA1 axis

> **NIH NIH R01** · CHILDREN'S MERCY HOSP (KANSAS CITY, MO) · 2021 · $384,018

## Abstract

The overall 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) is less than
50%, and ~75% of human HNSCC cases have mutations in the tumor suppressor p53. The vast majority of
p53 mutations are missense mutations that show oncogenic activities, with strong correlation with poor
prognosis in patients with HNSCC. Recent evidence indicates that stabilization of mutant p53 (mutp53) in
tumors is crucial for its oncogenic activities, while its knockdown attenuates tumor progression. Although there
are numerous publications on the function and regulation of wild-type p53 (wtp53), little is known about
mechanisms controlling mutp53 levels in tumors and the workable strategies that induce mutp53 degradation.
The goal of this proposal is to discover efficient strategies to specifically degrade mutp53 in HNSCC and
elucidate the underlying mechanisms. To identify compounds that reduce mutp53 levels, we performed high
throughput screening of chemical libraries and identified “statins”, a class of drugs that inhibit cholesterol
production, as degradation inducers of structurally misfolded mutp53 proteins. Statins showed minimal effects
on wtp53 and DNA contact mutp53 with native structure. Reduction in mevalonte-5-phosphate (MVP), but not
other metabolites in the mevalonate (MV) pathway, triggered mutp53 degradation by CHIP ubiquitin ligase in a
protein prenylation-independent manner. Statins also inhibited binding of mutp53 to DNAJA1, a molecular
chaperone of the Hsp40 family which plays a role in refolding of misfolded proteins. Indeed, mutp53
degradation by statins was nullified by MVP supplementation, as well as by DNAJA1 overexpression. These
data suggest that MVP positively regulates the DNAJA1-mutp53 binding and that DNAJA1 stabilizes misfolded
mutp53. However, it is still unclear how reduced MVP leads to inhibition of DNAJA1-mutp53 binding. Based on
our compelling preliminary data showing that reduction in MVP by knockdown of mevalonate kinase (MVK)
increased acetylation of mutp53, we hypothesize that acetylation of mutp53 upon MVP reduction inhibits the
mutp53-DNAJA1 binding, which promotes mutp53 degradation, leading to tumor suppression. We will test this
hypothesis and establish the role of DNAJA1 in the malignant progression of HNSCC cells. In Aim 1, we will
determine the mechanism by which reduced MVP leads to inhibited binding of mutp53 with DNAJA1 to induce
mutp53 degradation and tumor suppression. In Aim 2, we will test the hypothesis that DNAJA1 promotes
HNSCC progression in a misfolded mutp53-dependent manner. In Aim 3, we will characterize potential
DNAJA1 inhibitors identified through molecular docking studies for their abilities to bind to DNAJA1, induce
mutp53 degradation, and reduce the malignant properties of HNSCC cells. Completion of this study will reveal
a novel mechanism of mutp53 stabilization via unexpected functional link between MVP and DNAJA1 and will
establish the MV pathway and DNAJA1 as nov...

## Key facts

- **NIH application ID:** 10320158
- **Project number:** 7R01CA214916-04
- **Recipient organization:** CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
- **Principal Investigator:** Tomoo Iwakuma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,018
- **Award type:** 7
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320158

## Citation

> US National Institutes of Health, RePORTER application 10320158, Control of mutant p53 stability via the mevalonate pathway-DNAJA1 axis (7R01CA214916-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10320158. Licensed CC0.

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