2. Academic Validation
  3. PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility

PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility

  • J Exp Clin Cancer Res. 2024 May 15;43(1):144. doi: 10.1186/s13046-024-03064-1.
Nan Jing # 1 2,  Xinxing Du # 3,  Yu Liang # 4,  ZhenKeke Tao 1,  Shijia Bao 1,  Huixiang Xiao 1,  Baijun Dong 3,  Wei-Qiang Gao 5 6,  Yu-Xiang Fang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Med-X Research Institutes, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 3 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 4 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 5 State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China. gao.weiqiang@sjtu.edu.cn.
  • 6 Med-X Research Institutes, Shanghai Jiao Tong University, Shanghai, 200030, China. gao.weiqiang@sjtu.edu.cn.
  • 7 State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China. fyx2003@sjtu.edu.cn.
  • # Contributed equally.
PMID: 38745318 DOI: 10.1186/s13046-024-03064-1
Abstract

Background: Neuroendocrine prostate Cancer (NEPC) is a lethal subset of prostate Cancer which is characterized by neuroendocrine differentiation and loss of Androgen Receptor (AR) signaling. Growing evidence reveals that cell lineage plasticity is crucial in the failure of NEPC therapies. Although studies suggest the involvement of the neural transcription factor PAX6 in drug resistance, its specific role in NEPC remains unclear.

Methods: The expression of PAX6 in NEPC was identified via bioinformatics and immunohistochemistry. CCK8 assay, colony formation assay, tumorsphere formation assay and Apoptosis assay were used to illustrate the key role of PAX6 in the progression of in vitro. ChIP and Dual-luciferase reporter assays were conducted to confirm the binding sequences of AR in the promoter region of PAX6, as well as the binding sequences of PAX6 in the promoter regions of STAT5A and MET. For in vivo validation, the xenograft model representing NEPC subtype underwent pathological analysis to verify the significant role of PAX6 in disease progression. Complementary diagnoses were established through public clinical datasets and transcriptome Sequencing of specific cell lines. ATAC-seq was used to detect the chromatin accessibility of specific cell lines.

Results: PAX6 expression was significantly elevated in NEPC and negatively regulated by AR signaling. Activation of PAX6 in non-NEPC cells led to NE trans-differentiation, while knock-down of PAX6 in NEPC cells inhibited the development and progression of NEPC. Importantly, loss of AR resulted in an enhanced expression of PAX6, which reprogramed the lineage plasticity of prostate Cancer cells to develop NE phenotypes through the MET/STAT5A signaling pathway. Through ATAC-seq, we found that a high expression level of PAX6 elicited enhanced chromatin accessibility, mainly through attenuation of H4K20me3, which typically causes chromatin silence in Cancer cells.

Conclusion: This study reveals a novel neural transcription factor PAX6 could drive NEPC progression and suggest that it might serve as a potential therapeutic target for the management of NEPC.

Keywords

Lineage plasticity; Neuroendocrine prostate cancer; PAX6; STAT5A.

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