Vismodegib regulates microenvironment of basal cell carcinoma <italic style="font-style: italic">via</italic> BRD9-mediated Hedgehog and PD-L1 signaling

WANG Hao; ZHANG Lei; LI Junlong; LI Xintong; SUN Meiyan

doi:10.16016/j.2097-0927.202508025

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Vismodegib regulates microenvironment of basal cell carcinoma via BRD9-mediated Hedgehog and PD-L1 signaling

Basic Medicine | 更新时间：2025-11-13

- Vismodegib regulates microenvironment of basal cell carcinoma via BRD9-mediated Hedgehog and PD-L1 signaling
- Journal of Army Medical University Vol. 47, Issue 21, Pages: 2641-2651(2025)
- 作者机构：
  
  吉林医药学院检验学院，吉林吉林
- 作者简介：
  
  SUN Meiyan， E-mail： sunmy990@163.com
- 基金信息：
  
  the General Program of Natural Science Foundation of Jilin Province(YDZJ202301ZYTS442);the Key Research and Development Project of Jilin Province(20240305094YY);the College Student Innovation and Entrepreneurship Training Program of Jilin Province(S202313706019)
- DOI：10.16016/j.2097-0927.202508025
  CLC： R739.5;R966;R979.19
- Received：10 August 2025，
  
  Revised：2025-10-19，
  
  Accepted：20 October 2025，
  
  Published：15 November 2025
- 稿件说明：
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王皓，张磊，李君龙，等.维莫德吉通过BRD9介导的PD-L1调控基底细胞癌微环境［J］.陆军军医大学学报，2025，47（21）：2641-2651.DOI：10.16016/j.2097-0927.202508025.

WANG H，ZHANG L，LI J L，et al.Vismodegib regulates microenvironment of basal cell carcinoma via BRD9-mediated Hedgehog and PD-L1 signaling［J］.J Army Med Univ，2025，47（21）：2641-2651.DOI：10.16016/j.2097-0927.202508025.
王皓，张磊，李君龙，等.维莫德吉通过BRD9介导的PD-L1调控基底细胞癌微环境［J］.陆军军医大学学报，2025，47（21）：2641-2651.DOI：10.16016/j.2097-0927.202508025. DOI：

WANG H，ZHANG L，LI J L，et al.Vismodegib regulates microenvironment of basal cell carcinoma via BRD9-mediated Hedgehog and PD-L1 signaling［J］.J Army Med Univ，2025，47（21）：2641-2651.DOI：10.16016/j.2097-0927.202508025. DOI：

摘要

目的

探讨维莫德吉（vismodegib，Vis）通过染色质重塑因子BRD9影响基底细胞癌（basal cell carcinoma， BCC）发生发展的分子机制，分析BRD9在BCC中的表达特征及其与免疫检查点PD-L1及刺猬蛋白（Hedgehog，Hh）信号通路的关系。

方法

①通过SKH-1无毛背景的Ptch1

+/-

；LacZ报告基因小鼠构建紫外线B（ultraviolet B，UVB）诱导的BCC模型，并给予Vis干预。通过X-gal染色、免疫组化、免疫荧光和Western blot检测肿瘤组织中BRD9与PD-L1的表达与定位，并评估免疫细胞浸润。②体外以小鼠BCC的ASZ001细胞株（简称ASZ细胞）进行Vis与BRD9降解剂（dBRD9）处理，并构建BRD9过表达细胞株；检测细胞活力及BRD9、PD-L1、Gli1、Ccnd1的蛋白与mRNA表达。同时开展染色质免疫沉淀-定量聚合酶链反应，在PD-L1启动子近端（P1）与上游活跃片段（P2）检测BRD9与H3K27ac的富集变化。

结果

①组织水平发现BRD9在BCC中呈显著阳性表达，肿瘤区域可见BRD9与PD-L1的共定位及免疫细胞浸润；而Vis显著抑制UVB诱导的小鼠BCC形成（

0.01），降低大体积肿瘤发生率并减少X-gal阳性病灶面积（

0.000 1），并下调BRD9的表达（

=0.024 9），减弱免疫细胞浸润。②细胞水平发现Vis处理降低ASZ细胞活力，下调BRD9、Gli1、Ccnd1的表达（

0.000 1）；dBRD9剂量依赖性抑制ASZ细胞活力，并降低PD-L1、Gli1、Ccnd1表达（

0.000 1）；BRD9过表达则提高上述分子水平（

0.000 1）。ASZ细胞中BRD9与H3K27ac在PD-L1启动子P1/P2位点富集，经dBRD9或Vis处理后，P1/P2位点的BRD9与H3K27ac富集水平均降低（

0.000 1）。

结论

BCC中BRD9维持PD-L1近端染色质活化并调节Hh/Gli1信号，促进免疫逃逸，Vis通过抑制Hh-BRD9-PD-L1通路重塑基底细胞癌微环境。

Abstract

Objective

To investigate how vismodegib (Vis) influences the pathogenesis of basal cell carcinoma (BCC)

via

chromatin remodeling factor

bromodomain containing protein 9 (BRD9)

and to analyze the expression profile of BRD9 in BCC and its relationship with the immune checkpoint

programmed cell death-1 ligand 1 (PD-L1) and the Hedgehog (Hh) signaling pathway.

Methods

① A UVB-induced BCC model was established in SKH-1 hairless background Ptch1

+/-

; LacZ reporter mice. Then the mice were treated with Vis

and those without treatment served as control. X-gal staining

immunohistochemistry (IHC) staining

immunofluorescence (IF) assay

and Western blotting were used to assess the expression and localization of BRD9 and PD-L1 in tumor tissues and to evaluate immune-cell infiltration. ②

In vitro

mouse BCC cell line ASZ001 (ASZ cells) were treated with Vis or a BRD9 degrader (dBRD9)

and BRD9-overexpressing cells were generated. Cell viability and the protein and mRNA levels of BRD9

PD-L1

Gli1

and cyclin D1 (Ccnd1) were measured. ChIP-qPCR was performed to examine BRD9 and H3K27ac enrichment at the PD-L1 promoter

including the promoter-proximal site (P1) and an upstream active segment (P2).

Results

① At the tissue level

BRD9 was highly expressed in BCC

and co-localization of BRD9 and PD-L1 was observed within tumor regions

with evident immune-cell infiltration. Vis markedly suppressed UVB-induced BCC formation

reduced the probability of large-volume tumors (by probability-density analysis)

decreased the X-gal-positive lesion area(

0.000 1)

down-regulated BRD9(

=0.024 9)

and attenuated immune-cell infiltration. ② At the cellular level

Vis treatment reduced cell viability and down-regulated BRD9

Gli1

and Ccnd1 in ASZ cells(

0.000 1). dBRD9 inhibited ASZ cell viability in a dose-dependent manner and decreased PD-L1

Gli1

and Ccnd1(

0.000 1)

whereas its overexpression increased the expression of these molecules(

0.000 1).

In ASZ cells

BRD9 and H3K27ac were enriched at the PD-L1 promoter P1/P2 regions. Treatment with dBRD9 or Vis reduced BRD9 and H3K27ac enrichment at P1/P2 regions(

0.000 1).

Conclusion

In BCC

BRD9 maintains chromatin activation at the proximal PD-L1 promoter and modulates Hh/Gli1 signaling

thereby promoting immune evasion. Vis remodels the tumor immune microenvironment by inhibiting the Hh-BRD9-PD-L1 axis.

关键词

Keywords

references

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⁰

Vismodegib regulates microenvironment of basal cell carcinoma via BRD9-mediated Hedgehog and PD-L1 signaling

DOI：10.16016/j.2097-0927.202508025

摘要

Abstract

关键词

Keywords

references