Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States.
Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United States.
Front Endocrinol (Lausanne). 2023 Mar 29;14:1093332. doi: 10.3389/fendo.2023.1093332. eCollection 2023.
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 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.
神经内分泌前列腺癌（NEPC）是一种侵袭性很强的前列腺癌亚型。NEPC 的特征是雄激素受体（AR）信号丢失和向小细胞神经内分泌（SCN）表型的转化，这导致对 AR 靶向治疗的耐药性。NEPC 在临床上、组织学上和基因表达上与其他 SCN 癌相似。在这里，我们利用来自癌症依赖图谱（DepMap）的各种癌细胞系的 SCN 表型评分和基因缺失筛选，来鉴定 NEPC 的脆弱性。我们发现了转录因子 ZBTB7A，它是促进 NEPC 进展的候选物。具有高 SCN 表型评分的癌细胞对 RET 激酶活性具有强烈的依赖性，这些细胞中的 RET 和 ZBTB7A 依赖性之间存在高度相关性。利用来自患者样本的全转录组测序数据的信息建模，我们在 NEPC 与前列腺腺癌中鉴定了 ZBTB7A 的不同基因网络模式。具体来说，我们观察到 ZBTB7A 与促进细胞周期进展的基因，包括调节凋亡的基因，有很强的关联。在 NEPC 细胞系中沉默 ZBTB7A 证实了对 ZBTB7A 的依赖性，从而抑制了细胞周期中的 G1/S 转换，并诱导了细胞凋亡。总的来说，我们的结果强调了 ZBTB7A 在 NEPC 中的致癌功能，并强调了 ZBTB7A 作为针对 NEPC 肿瘤的有前途的治疗策略的价值。
