ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer
Song Yi Bae1, Hannah E Bergom2,3, Abderrahman Day2,3,4
1Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States.
Abstract:
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer. NEPC is characterized by the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which results in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and in gene expression. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency on RET kinase activity with a high correlation between RET and ZBTB7A dependencies in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we identified distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression, including apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency on ZBTB7A for cell growth via suppression of the G1/S transition in the cell cycle and induction of apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors.
Insights
Neuroendocrine prostate cancer (NEPC) progresses due to the transcription factor ZBTB7A. Targeting ZBTB7A suppresses NEPC cell growth by halting cell cycle progression and inducing apoptosis, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive subtype resistant to standard therapies.
- NEPC shares characteristics with small-cell neuroendocrine (SCN) carcinomas, suggesting common vulnerabilities.
- Identifying NEPC-specific vulnerabilities is crucial for developing effective treatments.
Purpose of the Study:
- To identify novel therapeutic targets and vulnerabilities in NEPC.
- To investigate the role of the transcription factor ZBTB7A in NEPC progression.
- To explore the relationship between ZBTB7A, RET kinase, and SCN phenotypes in prostate cancer.
Main Methods:
- Utilized SCN phenotype scores and gene depletion screens from the Cancer Dependency Map (DepMap).
- Performed bioinformatic modeling of whole transcriptome sequencing data from patient samples.
- Validated ZBTB7A's function by gene silencing in NEPC cell lines.
Main Results:
- Discovered ZBTB7A as a key factor promoting NEPC progression.
- Found a strong correlation between ZBTB7A dependency and RET kinase activity in NEPC.
- Identified distinct ZBTB7A gene networking patterns in NEPC, associated with cell cycle and apoptosis regulation.
- Demonstrated that ZBTB7A silencing inhibits NEPC cell growth by suppressing G1/S transition and inducing apoptosis.
Conclusions:
- ZBTB7A plays a significant oncogenic role in NEPC.
- ZBTB7A represents a promising therapeutic target for NEPC treatment.
- Understanding ZBTB7A's function provides insights into NEPC pathogenesis and treatment strategies.
