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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer
Daisuke Obinata1,2, Daigo Funakoshi1, Kenichi Takayama3
1Department of Urology, Nihon University School of Medicine, 30-1, Ooyaguchikamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
Abstract:
Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.
Insights
Transcription factor OCT1 targets neural genes STNB1 and PFN2 in androgen receptor-negative prostate cancer (PC). Targeting these genes inhibits PC cell migration and tumor growth, offering new therapeutic strategies for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) targeted therapies are standard for prostate cancer (PC).
- Tumors can develop resistance by becoming AR-negative via lineage plasticity.
- The role of transcription factor OCT1 in AR-negative PC remains unclear.
Purpose of the Study:
- To identify OCT1-regulated genes in AR-negative PC.
- To investigate the role of OCT1-target genes in PC progression.
- To explore potential therapeutic targets in AR-negative PC.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells.
- Identification and validation of OCT1 target genes (STNB1, PFN2).
- In vitro siRNA knockdown experiments and in vivo tumor growth studies.
Main Results:
- OCT1 regulates genes associated with neural precursor cell proliferation in AR-negative PC.
- STNB1 and PFN2 are highly expressed in human AR-negative PC tissues.
- Knockdown of STNB1 and PFN2 inhibited AR-negative PC cell migration; PFN2 knockdown significantly reduced tumor growth in vivo.
Conclusions:
- OCT1 targets neural genes STNB1 and PFN2 in AR-negative PC.
- STNB1 and PFN2 play critical roles in AR-negative PC cell migration and tumor growth.
- These findings identify novel therapeutic targets for advanced prostate cancer.
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