# Hepatic stellate cell regulation of metastatic growth in the liver

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $368,125

## Abstract

Liver metastasis is dependent on bidirectional interactions between cancer cells and the microenvironment
of the liver. TGF-β, released from cancer cells and other cells within the liver, induces activation of hepatic
stellate cells (HSCs) into tumor-promoting myofibroblasts (MFs). The long-term goal of our program is to
define mechanisms governing HSC activation and develop strategies to target HSCs. In this application, we
focus on E1A binding protein p300 (p300), an acetyltransferase with a poorly defined role in HSCs and
amenable to inhibition by small molecules. Our Preliminary Data demonstrate that (1) p300 resides in both
cytoplasm and nucleus of HSCs, (2) p300 knockdown (KD) or pharmacological inhibition inhibits nuclear
translocation of SMADs and MF activation of HSCs, (3) TGF-β1 induces a cytoplasmic
p300/Importin7/8/SMADs complex and a nuclear p300/SMADs/TAZ complex, leading to the expression of a
fibrogenic gene set including α-smooth muscle actin, and (4) in a tumor/HSC coimplantation mouse model,
p300 KD impairs paracrine effects of HSCs on promoting tumor growth. These novel findings have led to the
Central Hypothesis that p300 promotes HSC activation and a prometastatic liver microenvironment by
facilitating TGF-β-induced nuclear translocation of SMADs and transcription of TGF-β target genes. Three
Specific Aims are proposed to test the hypothesis. Aim 1 focuses on how p300 assembles a cytoplasmic
p300/Importin7/8/SMADs complex to promote TGF-β-stimulated nuclear transport of SMADs. In vitro and cell-
based studies, p300 mutants and a p300 inhibitor C646 will be used to test that p300 phosphorylation by
TGFβ1, the nuclear localization signal and acetyltransferase activity of p300 are required for TGFβ1-stimulated
p300/Importin7/8/SMADs interactions, SMAD nuclear transport and MF activation of HSCs. Aim 2 studies
epigenetics by which the p300/SMADs/TAZ complex regulates MF activation of HSCs. We will test the
hypothesis that TGFβ1 induces TAZ acetylation by p300 and suppresses TAZ ubiquitination, thereby
stabilizing TAZ and the p300/SMADs/TAZ complex. Additionally, a focused study (ChIP assays) and a
complementary genome-wide analyzing approach (ChIP sequencing) will be used to interrogate how the
p300/SMADs/TAZ complex facilitates TGFβ-induced gene transcription. Aim 3 focuses on in vivo role of p300
for HSC activation and liver metastasis. Conditional p300 knockout mice, portal vein tumor implantation and in
vivo tumor imaging technique will be used to study if p300 knockout in MF/activated-HSCs or pharmacological
inhibition of p300 abrogates liver metastatic growth in mice. Our studies will yield novel mechanistic insights
into MF activation of HSCs and help identify new targets and interventions to prevent and treat metastatic liver
disease.

## Key facts

- **NIH application ID:** 10064074
- **Project number:** 5R01CA160069-11
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** NINGLING KANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,125
- **Award type:** 5
- **Project period:** 2011-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064074

## Citation

> US National Institutes of Health, RePORTER application 10064074, Hepatic stellate cell regulation of metastatic growth in the liver (5R01CA160069-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064074. Licensed CC0.

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