# High Mobility Group A1 Chromatin Regulators in Colon Carcinogenesis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $356,797

## Abstract

ABSTRACT
Background: We propose to elucidate molecular mechanisms mediated by High Mobility Group A1
(HMGA1) chromatin remodeling proteins during colorectal carcinogenesis. The HMGA1 gene is highly
expressed during embryogenesis, but silenced postnatally in most adult tissues. HMGA1 is also
overexpressed in diverse, poorly differentiated cancers and high levels portend adverse outcomes. HMGA1
proteins modulate gene expression by “opening” chromatin and recruiting transcriptional complexes to DNA.
While it is clear that chromatin regulators help to govern nuclear architecture and cell fate decisions, the
underlying mechanisms are poorly understood. Here, we focus on HMGA1 in colorectal cancer (CRC).
Our scientific premise that HMGA1 fosters tumor progression in CRC is based on the following preliminary
results: 1) HMGA1 is highly overexpressed in CRC compared to non-malignant colonic epithelium, 2)
Silencing HMGA1 blocks oncogenic properties, prevents metastatic progression, and depletes cancer stem
cells in preclinical CRC models, 3) In transgenic mice, Hmga1 overexpression: a) induces hyperproliferation,
aberrant crypt formation, and premalignant polyposis in small and large intestines, and, b) expands the small
intestinal stem cell (ISC) pool by amplifying Wnt signals (Xian et al, Nature Comm; 2017), 5) Surprisingly,
Hmga1 also helps to “build” a stem cell niche by inducing Sox9 to generate Paneth cells, which support and
nurture small ISCs, 6) HMGA1 and SOX9 are positively correlated in human colon epithelium and both
become markedly up-regulated in colon cancer, and, 7) Inflammatory signals and procarcinogenic bacteria
associate with Hmga1 expression in preclinical tumor models.
Together, these intriguing results support the following hypotheses: 1) Hmga1 is required for normal
stem cell function and tissue homeostasis in colonic epithelium, 2) Deregulated HMGA1 disrupts this
equilibrium and drives carcinogenesis and tumor progression through aberrant changes in chromatin structure
and gene expression, 3) Inflammatory signals and specific pro-carcinogenic bacteria induce HMGA1 to drive
tumor progession, and, 4) Identifying mechanisms linked to HMGA1 overexpression will reveal novel pathways
that could be modulated to treat, or even prevent, colon carcinogenesis.
Aims/Approach: To test this, we propose the following Specific Aims: 1) To define oncogenic and stem cell
phenotypes dependent upon HMGA1 in colonic epithelium, 2) To elucidate epigenetic alterations and genetic
pathways through which HMGA1 functions during carcinogenesis, and, 3) To determine whether targeting
Hmga1 is effective in mitigating or preventing colon carcinogenesis in preclinical models.
Impact: We expect to elucidate mechanisms that induce HMGA1 as well as downstream pathways governed
by HMGA1 in CRC. This work could reveal a new paradigm for colon cancer pathogenesis and lead to
novel approaches to treat, or even prevent, this formidable cancer.

## Key facts

- **NIH application ID:** 10197847
- **Project number:** 5R01CA232741-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Linda M S Resar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,797
- **Award type:** 5
- **Project period:** 2018-07-24 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197847

## Citation

> US National Institutes of Health, RePORTER application 10197847, High Mobility Group A1 Chromatin Regulators in Colon Carcinogenesis (5R01CA232741-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197847. Licensed CC0.

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