# UCHL5 as a regulator and therapeutic target in metastatic melanoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $403,228

## Abstract

Melanoma is a major world health problem with most deaths occurring due to metastatic
spread of the disease. Although genetic basis of melanoma formation has been well established
whether metastatic progression of melanoma is driven by genetic or epigenetic events remains
unclear. With a hypothesis that epigenetic events may be a key driving force for metastatic
progression, we performed an in vivo gain-of-function screen that identified 10 epigenetic
regulators as drivers of melanoma metastasis. In this proposal, we focus on one of the top hits -
UCHL5 - which is a deubiquitinase and a mammalian specific subunit of Ino80 chromatin
remodeling complex. Using in vitro and in vivo validation experiments, we have verified role of
UCHL5 in promoting melanoma invasion and metastasis. Importantly, our preliminary studies
show that UCHL5 involves its deubiquitinase activity as well as its association with Ino80 in
promotion of invasion. In addition, we find that UCHL5 may regulate important pro-metastatic
pathways such as RhoA-LIMK-Cofilin and SLIT-ROBO signaling via direct regulation of
ARHGAP29 and SLIT2 respectively. Therefore, the objective of this proposal is to examine the
contribution of UCHL5 and its regulation of epigenome reprogramming in driving melanoma
metastasis. In the first aim, we propose to characterize UCHL5 mediated epigenome
reprogramming using human melanoma cultures in conjunction with animal models and cutting-
edge epigenomic technologies. We will assess dynamics of nucleosome position and
reprogramming of superenhancer elements by UCHL5 and assess contribution of Ino80 as well
as YAP1, which we have identified as a novel interactor of UCHL5. In the second aim, we will
study signaling events downstream of UCHL5 with a focus on ARHGAP29 mediated regulation
of RhoA-LIMK-Cofilin signaling and actin dynamics. In the third aim, we propose to examine
therapeutic utility of UCHL5 inhibition alone as well as in combination with current standard-of-
care melanoma therapies in pre-clinical transgenic animal models of metastatic melanoma.
Together, our proposal will not only provide new insights into the epigenetic mechanisms driving
melanoma metastasis but also provide proof-of-concept evidence for use of UCHL5 inhibitors as
a therapeutic strategy in metastatic melanoma.

## Key facts

- **NIH application ID:** 10402825
- **Project number:** 5R01CA245395-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Kunal Rai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,228
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402825

## Citation

> US National Institutes of Health, RePORTER application 10402825, UCHL5 as a regulator and therapeutic target in metastatic melanoma (5R01CA245395-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10402825. Licensed CC0.

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