# Targeting Transcriptional Co-repressor CoREST Complex in Melanoma

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2021 · $398,711

## Abstract

Precise control of gene transcription patterns, mediated by chromatin structural changes, is essential for cell
identity preservation that is disrupted in cancer cells. The CoREST complex, a multi-protein complex of
histone-modifying enzymes, functions as a transcriptional co-repressor by facilitating formation of repressive
chromatin. The CoREST complex contains two key histone modifying enzymes, lysine-specific histone
demethylase 1 (LSD1) and histone deacetylase 1 and 2 (HDAC1 and HDAC2) held together by the CoREST
scaffolding protein. These enzymes are typically up-regulated in cancer, suggesting the CoREST complex is a
specific target for cancer therapy. The goal of this proposed study is to molecularly define the CoREST
complex as a therapeutic target for cancer. We recently developed a small molecule inhibitor (corin2) of the
CoREST complex. Corin2 is a dual inhibitor of LSD1 and HDACs1/2 in the CoREST complex and shows high
potency anti-proliferative effects against many cancer cell types when screened against the NCI 60 panel, with
particular efficacy versus human melanomas. Our preliminary data suggests that the CoREST complex
activates c-MYC/E2F-stimulated target genes associated with cell cycle progression and proliferation. In
contrast, genes encoding the BMP/SMAD membrane-bound ligand-dependent nuclear receptors, which are
known for promoting cellular differentiation, are transcriptionally silenced by the CoREST complex. The anti-
proliferative role of the TGF-β/BMP-mediated SMAD signaling pathway is well documented; however, this
function is often lost in many cancer cells. Here, we hypothesize that the CoREST complex induces disruption
of BMP/SMAD driven anti-proliferative/differentiation signals resulting in increased transcriptional activation of
the MYC/E2F-dependent proliferation gene network. In this way, blocking the CoREST/MYC proliferative gene
transcription network circuit is expected to be an effective strategy in cancer. To test this hypothesis, we will
perform the following aims using melanoma as a target cancer model: 1) analyze genome-wide effects of
corin2 to discover the CoREST complex target gene signature and its correlation with the c-MYC/E2F target
transcription network, 2) define the role of the CoREST complex in BMP/SMAD signaling and the switch from a
differentiation/tumor- suppressive phenotype to cell growth phenotype, 3) evaluate corin2 as an epigenetic
anti-tumor agent by targeting the transcriptional regulatory mechanisms of the c-MYC/E2F transcription
network. To accomplish these aims, we will use the small molecule CoREST inhibitor, corin2, as well as a
series of chemically-related analogs; a genetically engineered mouse melanoma model; and human melanoma
tissue specimens. These proposed studies will extend our knowledge of the chromatin repressive CoREST
complex and its roles in regulating a cell proliferative gene transcription network. In this manner, this proposal
will provide a mechanistic ration...

## Key facts

- **NIH application ID:** 10221630
- **Project number:** 5R01CA212639-05
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Byungwoo Ryu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,711
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221630

## Citation

> US National Institutes of Health, RePORTER application 10221630, Targeting Transcriptional Co-repressor CoREST Complex in Melanoma (5R01CA212639-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10221630. Licensed CC0.

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