麦克尔细胞聚病毒（MCPyV）与大约80%的麦克尔细胞癌（MCC）病例相关，MCC是一种侵袭性的皮肤癌。在过去的二十年里，MCC的发病率翻了三倍，但目前有效的靶向治疗方法很少。对MCPyV生命周期和致癌机制的更深入理解是揭示MCC预防和治疗新策略的关键。MCPyV的感染和致癌依赖于早期病毒致癌蛋白的表达，这些蛋白推动病毒生命周期和MCPyV+ MCC肿瘤细胞的生长。迄今为止，调控MCPyV致癌基因转录的分子机制大多未被表征。在本研究中，我们调查了MCPyV早期转录的调控方式，以支持病毒感染和MCC肿瘤发生。我们的研究确定了多个细胞因子在MCPyV基因表达控制中的作用。抑制剂筛选实验揭示了组蛋白乙酰转移酶p300和CBP正调控MCPyV转录。他们通过共同激活转录因子NF-κB调控病毒基因表达，该转录因子与病毒基因组结合，以负反馈环形式严格控制MCPyV致癌基因表达。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能够有效阻断MCPyV肿瘤抗原的表达和MCPyV+ MCC细胞增殖。总之，我们的研究确定了调控MCPyV转录的关键细胞因子，为了解调控MCPyV转录的机制、定义其传染性宿主细胞竞争性以及致癌潜力提供了基础。我们的研究还通过特异性阻断MCPyV致癌基因表达和MCC肿瘤生长鉴定了一种新颖的MCPyV+ MCC治疗策略。 版权：© 2023 杨等人。本文是根据创作共享署名许可下的开放获取文章，请在任何媒介中自由使用、分享和复制，只要保留原作者和出处的署名。

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.Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.