HIV1-TAT interacting protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.

HIV1-TAT相互作用蛋白（TIP60）是单倍型肿瘤抑制剂。但是，尚不清楚其赋予其抑癌能力的潜在机制。它在病毒诱导的癌症中起着至关重要的作用，其中TIP60下调人乳头瘤病毒（HPV）癌蛋白E6的表达，进而破坏TIP60的稳定性。这使我们对在癌蛋白靶向的病毒感染的情况下确定TIP60的作用产生了兴趣。通过染色质免疫沉淀，表达分析和质谱等一系列分子生物学技术，我们建立了TIP60在抑制人类端粒酶复合物催化亚基TERT（永生化的关键驱动因素）的表达中迄今未知的作用。TIP60在K639处使Sp1乙酰化，从而抑制Sp1与K1的结合。TERT启动子。我们发现，TIP60介导的HPV诱导子宫颈癌的生长抑制部分是由于Sp1乙酰化对TERT的抑制作用所介导的。总而言之，我们的研究确定了TIP60催化活性的新型底物和在病毒诱导的恶性肿瘤中作用于TERT启动子的独特抑制机制。