成人T细胞白血病/淋巴瘤(ATL)是由人T细胞白血病病毒1型(HTLV-1)感染引起的侵袭性恶性肿瘤。HTLV-1通过与参与细胞增殖和转化的信号通路相互作用发挥其致癌功能。Hippo/YAP通路的失调与多种癌症有关,包括病毒诱导的恶性肿瘤。在本研究中,我们观察到YAP的表达,这是河马信号的关键效应,通过HTLV-1Tax蛋白的作用在ATL细胞中升高。YAP转录活性在HTLV-1感染的细胞和ATL患者中显著增强。此外,Tax通过涉及NF-κB/p65途径的机制激活YAP蛋白。作为Hippo和NF-κB途径之间的这种串扰的机制,我们发现p65消除了YAP和LATS1之间的相互作用,从而抑制了YAP的磷酸化,抑制YAP的泛素化依赖性降解,和YAP核积累。最后,敲除YAP抑制ATL细胞的体外增殖和ATL移植小鼠的肿瘤形成。一起来看,我们的结果表明,p65诱导的YAP激活对于ATL发病机制至关重要,并暗示YAP是ATL治疗的潜在治疗靶点.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. HTLV-1 exerts its oncogenic functions by interacting with signaling pathways involved in cell proliferation and transformation. Dysregulation of the Hippo/YAP pathway is associated with multiple cancers, including virus-induced malignancies. In the present study, we observe that expression of YAP, which is the key effector of Hippo signaling, is elevated in ATL cells by the action of the HTLV-1 Tax protein. YAP transcriptional activity is remarkably enhanced in HTLV-1-infected cells and ATL patients. In addition, Tax activates the YAP protein via a mechanism involving the NF-κB/p65 pathway. As a mechanism for this cross talk between the Hippo and NF-κB pathways, we found that p65 abrogates the interaction between YAP and LATS1, leading to suppression of YAP phosphorylation, inhibition of ubiquitination-dependent degradation of YAP, and YAP nuclear accumulation. Finally, knockdown of YAP suppresses the proliferation of ATL cells in vitro and tumor formation in ATL-engrafted mice. Taken together, our results suggest that p65-induced YAP activation is essential for ATL pathogenesis and implicate YAP as a potential therapeutic target for ATL treatment.