Characterization of molecular mechanisms driving Merkel cell polyomavirus oncogene transcription and tumorigenic potential.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-30 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011598
June F Yang, Wei Liu, Jianxin You
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引用次数: 0

Abstract

Merkel cell polyomavirus (MCPyV) is associated with approximately 80% of cases of Merkel cell carcinoma (MCC), an aggressive type of skin cancer. The incidence of MCC has tripled over the past twenty years, but there are currently very few effective targeted treatments. A better understanding of the MCPyV life cycle and its oncogenic mechanisms is needed to unveil novel strategies for the prevention and treatment of MCC. MCPyV infection and oncogenesis are reliant on the expression of the early viral oncoproteins, which drive the viral life cycle and MCPyV+ MCC tumor cell growth. To date, the molecular mechanisms regulating the transcription of the MCPyV oncogenes remain largely uncharacterized. In this study, we investigated how MCPyV early transcription is regulated to support viral infection and MCC tumorigenesis. Our studies established the roles of multiple cellular factors in the control of MCPyV gene expression. Inhibitor screening experiments revealed that the histone acetyltransferases p300 and CBP positively regulate MCPyV transcription. Their regulation of viral gene expression occurs through coactivation of the transcription factor NF-κB, which binds to the viral genome to drive MCPyV oncogene expression in a manner that is tightly controlled through a negative feedback loop. Furthermore, we discovered that small molecule inhibitors specifically targeting p300/CBP histone acetyltransferase activity are effective at blocking MCPyV tumor antigen expression and MCPyV+ MCC cell proliferation. Together, our work establishes key cellular factors regulating MCPyV transcription, providing the basis for understanding the largely unknown mechanisms governing MCPyV transcription that defines its infectious host cell tropism, viral life cycle, and oncogenic potential. Our studies also identify a novel therapeutic strategy against MCPyV+ MCC through specific blockage of MCPyV oncogene expression and MCC tumor growth.

Abstract Image

Abstract Image

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驱动Merkel细胞多瘤病毒癌基因转录和致瘤潜能的分子机制表征。
默克尔细胞多瘤病毒(MCPyV)与大约80%的默克尔细胞癌(MCC)(一种侵袭性皮肤癌症)病例有关。MCC的发病率在过去20年中增加了两倍,但目前很少有有效的靶向治疗。需要更好地了解MCPyV的生命周期及其致癌机制,以揭示预防和治疗MCC的新策略。MCPyV感染和致癌依赖于早期病毒癌蛋白的表达,这些蛋白驱动病毒的生命周期和MCPyV+MCC肿瘤细胞的生长。到目前为止,调节MCPyV癌基因转录的分子机制在很大程度上仍不明确。在这项研究中,我们研究了MCPyV早期转录是如何被调节以支持病毒感染和MCC肿瘤发生的。我们的研究确定了多种细胞因子在控制MCPyV基因表达中的作用。抑制剂筛选实验表明,组蛋白乙酰转移酶p300和CBP正调控MCPyV的转录。它们对病毒基因表达的调节是通过转录因子NF-κB的共同激活来实现的,转录因子与病毒基因组结合,以通过负反馈回路严格控制的方式驱动MCPyV癌基因的表达。此外,我们发现特异性靶向p300/CBP组蛋白乙酰转移酶活性的小分子抑制剂可有效阻断MCPyV肿瘤抗原表达和MCPyV+MCC细胞增殖。我们的工作共同建立了调节MCPyV转录的关键细胞因子,为理解控制MCPyV的转录的未知机制提供了基础,这些机制定义了其感染宿主细胞的嗜性、病毒生命周期和致癌潜力。我们的研究还通过特异性阻断MCPyV癌基因表达和MCC肿瘤生长,确定了一种针对MCPyV+MCC的新治疗策略。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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