2. Academic Validation
  3. Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer

Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer

  • J Exp Clin Cancer Res. 2021 Jun 21;40(1):203. doi: 10.1186/s13046-021-01989-5.
Jingtong Zhang  # 1 2 3,  Qianghua Zhou  # 1 2 3,  Keji Xie  # 4,  Liang Cheng 1 2 3,  Shengmeng Peng 1 2 3,  Ruihui Xie 1 2 3,  Lixuan Liu 5,  Yangjie Zhang 1 2 3,  Wen Dong 1 3,  Jinli Han 1 3,  Ming Huang 1 2 3,  Yuelong Chen 1 6,  Tianxin Lin 7 8 9 10,  Jian Huang 11 12 13,  Xu Chen 14 15 16
Affiliations

Affiliations

  • 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, China.
  • 4 Department of Urology, Guangzhou First People's Hospital, Guangzhou, China.
  • 5 Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 7 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Guangzhou, China. lintx@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. lintx@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, China. lintx@mail.sysu.edu.cn.
  • 10 Department of Urology, The Affiliated Kashi Hospital, Sun Yat-sen University, Kashi, China. lintx@mail.sysu.edu.cn.
  • 11 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Guangzhou, China. huangj8@mail.sysu.edu.cn.
  • 12 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. huangj8@mail.sysu.edu.cn.
  • 13 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, China. huangj8@mail.sysu.edu.cn.
  • 14 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107th Yanjiangxi Road, Guangzhou, China. chenx457@mail.sysu.edu.cn.
  • 15 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. chenx457@mail.sysu.edu.cn.
  • 16 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, China. chenx457@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 34154613 DOI: 10.1186/s13046-021-01989-5
Abstract

Background: Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder Cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder Cancer.

Methods: We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA Sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition.

Results: First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 Inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced Apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner.

Conclusions: Our novel finding is that the WDR5 Inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing Apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential Anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.

Keywords

Bladder cancer; Chemosensitivity; Metastasis; OICR-9429; PD-L1; Target therapy; WDR5 inhibitor.

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