TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter

HIV1-TAT interactive 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（HIV1-TAT interactive protein, TIP60）是一种单倍剂量不足型肿瘤抑制因子。然而，赋予其肿瘤抑制功能的潜在分子机制仍未完全阐明。该蛋白在病毒诱导型癌症中发挥关键作用：TIP60可下调人类乳头瘤病毒（human papillomavirus, HPV）癌蛋白E6的表达，而E6反过来又会使TIP60的稳定性降低。这一现象促使我们探究TIP60在病毒感染情境中的作用——此时它会被癌蛋白靶向调控。本研究通过染色质免疫沉淀（Chromatin immunoprecipitation）、表达分析及质谱分析（mass spectrometry）等一系列分子生物学技术，证实了TIP60迄今未知的作用：它可抑制人类端粒酶复合物催化亚基（TERT）的表达，而TERT是细胞永生化的关键驱动因子。TIP60可在K639位点对Sp1蛋白进行乙酰化修饰，从而抑制Sp1与TERT启动子的结合。本研究发现，TIP60对HPV诱导宫颈癌的生长抑制作用，部分是通过Sp1乙酰化抑制TERT表达来实现的。综上，本研究发现了TIP60催化活性的全新底物，以及病毒诱导型恶性肿瘤中作用于TERT启动子的独特转录抑制机制。