# Regulating Gli Function in Hair Follicle Progenitors

> **NIH NIH R37** · STANFORD UNIVERSITY · 2022 · $463,232

## Abstract

Project Summary
Basal cell carcinoma (BCC), caused by the inappropriate activation of the hedgehog
(Hh) pathway, represents a common skin cancer that, while treated surgically, can also exhibit
rapid invasion and metastasis. While Smoothened inhibitors (Smoi) show efficacy, the majority of
advanced BCCs acquire resistance. 5ARO54780 showed that increased expression in BCCs of
the polarity kinase atypical protein kinase C (PRKCi) amplifies Gli activity and confers
resistance, although the mechanism remains unknown. PRKCi cooperates with histone
deacetylase 1 (HDAC1) to promote Gli deacetylation and chromatin association. A vicinal
proteomics approach led to the surprising identification that isoforms of the Lamina-Associated
Polypeptide 2 (LAP2) bind to the Gli zinc finger domain. Nuclear envelope tethered LAP2b and
an associated acetyl-lysine reader promote Gli accumulation at a site termed the paused nuclear
complex that protects Gli from degradation or nuclear export. By contrast, nucleoplasmic LAP2a
binds both HDAC1 and Gli allowing it to stably accumulate on chromatin. In turn, PRKCi
prevents LAP2a-HDAC1-GLI degradation while promoting switching from LAP2b to LAP2a. Now
in its 10th year, 5ARO54780 will test the overarching hypothesis that PRKCi-dependent Gli
deacetylation directs association with distinct LAP2 isoforms that amplify pathway activity in
resistant BCCs. We will: 1) Elucidate the structure and function of the Gli-LAP2b paused nuclear
complex as we identify the LAP2b functional domains required for Gli activity, identify
components of the Gli-LAP2b acetyl-lysine reader, and dissect how LAP2 regulates Gli
localization and mobility; 2) Elucidate the structure and function of the GLI-LAP2a activation
complex as we determine whether LAP2a requires Gli for colocalization, define the non-base
contact surface of LAP2-Gli1, and elucidate how PRKCi regulates LAP2a-HDAC1-Gli stability;
3) Establish resistance pathway efficacy and epistasis as we determine the prevalence of the
BCC resistance pathways and determine efficacy of the LAP2-LLD in human and mouse BCC
explants. Completion of the project will deepen our mechanistic insights into transcription factor
trafficking and regulation in the nucleus, help optimize rational BCC therapy, and identify new
therapeutic targets.

## Key facts

- **NIH application ID:** 10337188
- **Project number:** 5R37AR054780-14
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Anthony E Oro
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $463,232
- **Award type:** 5
- **Project period:** 2007-05-07 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337188

## Citation

> US National Institutes of Health, RePORTER application 10337188, Regulating Gli Function in Hair Follicle Progenitors (5R37AR054780-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337188. Licensed CC0.

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