NIR promotes progression of colorectal cancer through regulating RB
NIR promotes progression of colorectal cancer through regulating RB
复制标题
NIR通过调节RB促进结直肠癌进展
DOI：
10.1016/j.bbamcr.2020.118856
复制
发表时间：
2021-01-01
影响因子：
5.1
通讯作者：
Xing, Baocai
中科院分区：
文献类型：
--
作者：
Li, Yuan;Wang, Ling;Xing, Baocai
NIR是一种新的INHAT，负调控肿瘤抑制因子p53的转录活性。然而，NIR在肿瘤发生中是否依赖于p53的调节仍不清楚。在这里，我们报告说，近红外线促进大肠癌（CRC）的进展，通过调节RB功能。首先，我们发现NIR表达在人CRC组织中上调，并且与患者的不良预后显著相关。序列比对显示NIR在其INHAT-2结构域中含有RB结合基序LxCxE。我们证明NIR通过INHAT-2与CRC细胞中的RB相互作用，并通过蛋白酶体介导的途径促进RB降解。此外，全长GFP-NIR或GFP-NIR-INHAT 2促进RB的聚泛素化。此外，NIR抑制了INHAT-2对RB的乙酰化作用，表明NIR可能通过抑制RB的乙酰化而促进RB的降解。重要的是，内源性NIR在DNA损伤后下调，这与RB的总水平和乙酰化的上调一致。我们进一步表明，Flag-NIR抑制DNA损伤诱导的RB乙酰化。因此，近红外线的下调可能有助于维持DNA损伤下的细胞稳态。因此，NIR的耗尽抑制小鼠异种移植物中的细胞增殖和肿瘤生长。总之，我们证明NIR促进CRC进展部分通过抑制RB乙酰化和促进RB降解。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。
NIR, a novel INHAT, negatively regulates the transcription activity of tumor repressor p53. However, if NIR functions in the tumorigenesis dependent on the regulation of p53 remains unknown. Here, we report that NIR promotes progression of colorectal cancer (CRC) through regulating RB function. Firstly, we found that NIR expression is upregulated in the human CRC tissues and significantly associated with the poor outcome of the patients. Sequence alignment shows that NIR contains an RB-binding motif LxCxE in its INHAT-2 domain. We demonstrate that NIR interacts with RB via INHAT-2 in CRC cells and promotes RB degradation through proteasome-mediated pathway. Further, either full-length GFP-NIR or GFP-NIR-INHAT2 facilitates poly-ubiquitination of RB. In addition, NIR inhibits RB acetylation by INHAT-2, suggesting NIR might promote RB degradation through inhibiting RB acetylation. Importantly, endogenous NIR is downregulated upon DNA damage, which is consistent with the upregulation of total level and acetylation of RB. We further show that Flag-NIR inhibits DNA damage-induced RB acetylation. Thus, downregulation of NIR might contribute to maintain the cellular homeostasis under DNA damage. Consequently, depletion of NIR inhibits cell proliferation and tumor growth in mouse xenografts. Taken together, we demonstrate that NIR promotes CRC progression partially through inhibiting RB acetylation and promoting RB degradation. Targeting NIR may provide a potential therapeutic strategy for NIR-upregulated CRC patients.