# Remediating Ing4 tumor suppressor deficiency using a zebrafish model

> **NIH NIH P20** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $12,387

## Abstract

ABSTRACT 
The multifaceted nature of cancer results in a disease that is complicated and difficult to treat. One common 
characteristic of this disease is the ability of cancer cells to re-acquire stem-cell like traits resulting in aberrant 
gene expression and resistance to therapy. As the molecular networks that are frequently aberrant in cancer 
are also utilized by normal stem cells, it is critical to understand how these pathways and mechanisms function 
in stem cells and are harnessed by cancer cells to promote disease progression. Aberrant gene expression in 
tumors is often a result of oncogene expression or tumor suppressor inactivation. Tumor suppressors are 
particularly challenging to target as these proteins are often missing or present only at very low levels in tumor 
cells. Our lab has recently identified the tumor suppressor, ING4, a chromatin modifier and a transcriptional 
regulator containing a PHD finger domain, as a critical regulator of hematopoietic stem cell specification. ING4 
has been shown to be inactivated in several types of human cancer, including breast, prostate, colorectal, 
ovarian and lung cancers, astrocytomas, and hepatocellular carcinomas. Loss of ING4 expression is 
associated with a poor prognosis but the mechanisms of tumor-suppressive functions of ING4 are not yet fully 
understood. A potential mechanism of tumor suppressor activity of ING4 is through its negative regulation of 
the NF-κB pathway, implicated in carcinogenesis, tumor progression and drug resistance. We found that Ing4 
depletion in zebrafish stimulates NF-κB activity and NF-κB inhibition can rescue HSC deficiency caused by the 
loss of Ing4. Our proposed Specific Aims will use both genetic and pharmacological approaches, both in 
developing zebrafish and in ING4-deficient human tumor cells, to identify potential mechanisms for combating 
the loss of this protein in cancer. Aim 1 is to investigate the effects of Ing4 inactivation in zebrafish on gene 
expression and to determine if targeting of gene expression pathways that are upregulated upon loss of Ing4 
would rescue the effects of Ing4 inactivation on HSC specification in zebrafish. Aim 2 is to determine if small 
molecule inhibitors of the NF-κB and other upregulated pathways would rescue the effects of Ing4 loss of 
function in zebrafish. Aim 3 is to identify genes and pathways, inhibition of which remediates cellular effects of 
ING4 inactivation in mammalian tumor cells, by using the results of the analysis in zebrafish and of a genetic 
screen conducted in ING4-deficient human tumor cells. The success of the proposed study will serve as the 
basis for identifying drugs that could remediate phenotypic effects of the ING4 deficiency, with the ultimate goal 
of developing therapeutic strategies for cancers where ING4 has been inactivated.

## Key facts

- **NIH application ID:** 10403538
- **Project number:** 5P20GM109091-09
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Katie L Kathrein
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $12,387
- **Award type:** 5
- **Project period:** 2014-07-10 → 2023-12-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403538

## Citation

> US National Institutes of Health, RePORTER application 10403538, Remediating Ing4 tumor suppressor deficiency using a zebrafish model (5P20GM109091-09). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10403538. Licensed CC0.

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