# Endolysosomal-nuclear communication mediated through V-ATPase and NHE9 dependent epigenetic signaling

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $198,360

## Abstract

Tumors are exposed to constantly changing nutrient environments which creates metabolic stress that impairs
their growth and proliferation. Consequently, cancer cells evolve phenotypic adaptations to contend with this
nutrient flux that require epigenetic and transcriptional reprogramming. These phenotypic adaptations also can
affect tumor cell sensitivity to chemotherapeutic agents. How cytoplasmic organelles involved in nutrient
signaling exert their effects on the nuclear epigenome remains a fundamental problem to define since these
pathways are candidate therapeutic targets for anticancer drug development. The V-ATPase is an
evolutionarily conserved multimeric proton pump that acidifies the endolysosomal compartment to regulate
intracellular pH and activate essential nutrient signaling pathways. Na+/H+ exchanger (NHE) factors,
specifically NHE9, antagonize V-ATPase dependent endosomal acidification. NHE9 is overexpressed in many
tumors, and recent studies have demonstrated that NHE9 overexpression in glioblastoma (GBM) contributes
directly to tumorigenesis. Intriguingly, genetic screens in budding yeast identified both the V-ATPase and the
yeast NHE9 ortholog, Nhx1, as regulators of histone H3 and H4 (H3/H4) acetylation through unknown
mechanisms. Our preliminary data demonstrate that V-ATPase signaling in human GBM cells also regulates
H3/H4 acetylation, thus demonstrating that the V-ATPase is an evolutionarily conserved epigenetic regulator.
This project will test the innovative hypothesis that the V-ATPase and Nhx1/NHE9 regulate the endolysosomal-
nuclear communication required for epigenetic adaptation to altered nutrient states. Using yeast and human
GBM models, we will perform the following Specific Aims. In Aim I, we will identify the key nutrient signaling
pathways downstream of the V-ATPase controlling global H3/H4 acetylation, and then we will determine if this
involves repression of the sirtuin family of deacetylases or if it involves non-sirtuin mechanisms. We will test
specifically if V-ATPase dependent H3/H4 acetylation regulates the binding of ATP-dependent chromatin
remodeling enzymes important for transcription of metabolic genes. In Aim II, we will determine if V-ATPase
dependent H3/H4 acetylation controls the DNA damage response to alkylating agents, including the GBM
standard of care chemotherapeutic agent temozolomide (TMZ), by anchoring ATP-dependent nucleosome
remodeling enzymes onto chromatin. Upon the project's completion, we will have defined a novel paradigm by
which the endolysosomal compartment regulates nuclear epigenetic pathways critical for metabolic gene
expression and sensitivity to genotoxic stress.

## Key facts

- **NIH application ID:** 9957056
- **Project number:** 5R21CA233028-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Ronald Laribee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,360
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957056

## Citation

> US National Institutes of Health, RePORTER application 9957056, Endolysosomal-nuclear communication mediated through V-ATPase and NHE9 dependent epigenetic signaling (5R21CA233028-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957056. Licensed CC0.

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