# Role of KDM5A in pRB-mediated differentiation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $365,771

## Abstract

Abstract
Studies of one of the most important tumor suppressor genes, RB1, have transformed
the treatment of human cancer. This success was based on targeting E2F-responsive
genes that were deregulated as a direct consequence of dysfunctional pRB. However,
there is accumulating evidence of a multifaceted role of pRB and its involvement as a
major regulator in processes outside the cell cycle. In particular, we rediscovered one of
the first pRB-interacting proteins, KDM5A, in a screen for cellular factors critical for pRB
function during differentiation. We found that KDM5A is directly downstream of pRB in
the pathway, as decreasing KDM5A protein levels in RB-deficient cells was reminiscent
of the effects of reintroducing pRB: it increased the activity of cell-type-specific
transcription factors, and restored gene expression and morphological changes
associated with differentiation. KDM5A is a demethylase that reads and removes
methylation from lysine 4 on histone H3 (H3K4) at a subset of pRB target genes.
Surprisingly, we found that pRB function at the onset of differentiation converges on
activation of KDM5A target genes encoding mitochondrial components. Accordingly,
overexpression in Rb-deficient cells of a major regulator of mitochondrial functions,
PGC-1α, restored differentiation, phenocopying the reintroduction of pRB. In order to
mechanistically understand the link between mitochondrial metabolic regulation and the
induction of differentiation, we propose to study the RB pathway downstream of KDM5A:
(1) we will investigate which functions in the mitochondrion are necessary and sufficient
for differentiation rescue; (2) we will explore a therapeutic strategy for activation of
mitochondrial function in cells from RB-deficient small cell lung cancers; (3) we will
investigate whether there is a correlation between pRB deficiency and the mitochondrial
signature, and how this relates to patient prognosis; and (4) we will study how
mitochondrial genes are regulated by pRB, KDM5A and associated transcription factors.
The relevance of KDM5A inhibition to cancer cell metabolism and differentiation is of
great interest, as KDM5A is likely to be targeted by small-molecule inhibitors.

## Key facts

- **NIH application ID:** 10056210
- **Project number:** 5R01CA211095-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Elizaveta V Benevolenskaya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,771
- **Award type:** 5
- **Project period:** 2016-12-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056210

## Citation

> US National Institutes of Health, RePORTER application 10056210, Role of KDM5A in pRB-mediated differentiation (5R01CA211095-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10056210. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*