# Menin regulates colonic epithelial cell growth through LXR repression

> **NIH NIH R03** · UNIVERSITY OF PENNSYLVANIA · 2020 · $121,500

## Abstract

PROJECT SUMMARY
Despite many advances in diagnosis and treatment, colorectal cancer (CRC) remains one of the leading
causes of cancer-related morbidity and mortality worldwide. Understanding factors in the colonic epithelial that
promote colonic adenoma formation and subsequent development of CRC are of critical importance. We have
shown that menin, a nuclear scaffold protein that has both tumor suppressor and tumor promoter roles in a
highly tissue specific manner, is over-expressed in CRC compared to benign colonic epithelium, and unbiased
RNA-Seq revealed that menin inhibition leads to enhanced transcription of target genes of the liver X receptor
(LXR), therefore demonstrating that menin represses LXR-mediated gene transcription. The LXRs, including
LXRα and LXRβ, are nuclear receptors that are critical for maintaining cellular cholesterol homeostasis, and
increased LXR-mediated gene transcription can lead to suppression of CRC growth. However, the mechanism
whereby menin represses LXR-mediated gene transcription as well as the involvement of menin in progression
through the colon adenoma-carcinoma sequence is currently unknown and serves as the focus of this
application. Our data shows that LXR target genes are the most significantly upregulated after menin inhibition
in CRC cells, and that menin binds to LXR response elements (LXREs) with LXRα and inhibits the recruitment
of RNA polymerase II. Furthermore, the increase in LXR-mediated gene transcription induced by menin
inhibition has functional consequences, leading to decreased levels of cellular cholesterol in CRC cells and
enhancing sensitivity of CRC cells to lipid starvation. As the importance of the interaction between menin and
the LXRs in the colonic epithelial is uncertain, our findings lead to a novel hypothesis that menin
upregulation in the colonic epithelium inhibits LXR activity, enriches cellular cholesterol, and
promotes progression along the adenoma-carcinoma sequence. We will test this hypothesis using
innovative methods and novel strategies to define the mechanism whereby menin represses LXR-mediated
gene transcription. Furthermore, we will determine whether menin, and its repression of LXR-mediated
transcription, are important for promoting progression through the adenoma-carcinoma sequence in the colonic
epithelium both in vitro and in vivo. These experiments will provide important insights into the role of menin in
both the colonic epithelium and epithelial progression through the adenoma-carcinoma sequence. Moreover,
these experiments will serve as a platform for the development of future proposals that will have application to
CRC prevention and treatment. Additionally, it is expected that this R03 award will be critical to facilitating
future publication generation, a R01 grant application, and the PI's transition to independence.

## Key facts

- **NIH application ID:** 9936437
- **Project number:** 5R03DK120946-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Bryson William Katona
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $121,500
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936437

## Citation

> US National Institutes of Health, RePORTER application 9936437, Menin regulates colonic epithelial cell growth through LXR repression (5R03DK120946-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9936437. Licensed CC0.

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