A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-04-29 DOI:10.1038/s41388-025-03413-0

Prachi Walke, Jared D. W. Price, Frederick S. Vizeacoumar, Nickson Joseph, Vincent Maranda, Bari Chowdhury, Jay Patel, Yue Zhang, He Dong, Lara New, Ashtalakshmi Ganapathysamy, Li Hui Gong, Mary Lazell-Wright, Hussain Elhasasna, Kalpana K. Bhanumathy, Yuliang Wu, Yuzhuo Wang, Andrew Freywald, Anand Krishnan, Franco J. Vizeacoumar

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Abstract

Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression of MYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities of MYCN. Among the identified candidates, NEUROG2 emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells but significantly suppresses the growth of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that Neurog2-driven modulation of PTFs potentially contribute to NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.

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Neurog2在MYCN驱动的前列腺癌神经内分泌可塑性中的新作用。

神经内分泌前列腺癌（NEPC）由于其侵袭性进展和对常规治疗的耐药性，提出了一个巨大的临床挑战。NEPC的一个关键驱动因素是MYCN的过表达，MYCN是一种与神经内分泌肿瘤相关的癌基因。然而，直接抑制该基因编码的N-Myc蛋白的努力取得了有限的成功，从而阻碍了治疗的进步。为了克服这一障碍，我们使用等基因前列腺癌细胞系进行了无偏倚的全基因组筛选，以确定MYCN的合成脆弱性。在确定的候选者中，NEUROG2成为一个重要的候选者。Neurog2是一种前神经转录因子（PTF），在成年细胞的发育过程和反式分化中起着重要作用。我们的研究结果表明，在原位NEPC模型中，Neurog2缺失不会影响非恶性细胞，但会显著抑制mycn过表达细胞和肿瘤的生长。此外，我们的观察结果表明，neurog2驱动的ptf调节可能有助于NEPC的发展。因此，靶向Neurog2有望成为mycn过表达NEPC的有效治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.