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.

NIR是一种新型的INHAT，它负调控肿瘤抑制因子p53的转录活性。但是，NIR是否在肿瘤发生中依赖于p53的调控尚不清楚。在这里，我们报道NIR通过调节RB功能促进结直肠癌（CRC）的进展。首先，我们发现在人类CRC组织中NIR表达上调，并且与患者不良预后显着相关。序列比对表明，NIR在其INHAT-2域中包含一个RB结合基序LxCxE。我们证明，NIR通过CRC细胞中的INHAT-2与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-INHAT2促进RB的多泛素化。此外，NIR通过INHAT-2抑制RB乙酰化，提示NIR可能通过抑制RB乙酰化而促进RB降解。重要的是，内源性NIR在DNA损伤后被下调，这与RB的总水平和乙酰化的上调相一致。我们进一步表明，Flag-NIR抑制DNA损伤诱导的RB乙酰化。因此，NIR的下调可能有助于维持DNA损伤下的细胞稳态。因此，NIR的消耗会抑制小鼠异种移植物中的细胞增殖和肿瘤生长。综上所述，我们证明NIR通过抑制RB乙酰化和促进RB降解来部分促进CRC进展。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。这与RB的总水平和乙酰化的上调是一致的。我们进一步表明，Flag-NIR抑制DNA损伤诱导的RB乙酰化。因此，NIR的下调可能有助于维持DNA损伤下的细胞稳态。因此，NIR的消耗会抑制小鼠异种移植物中的细胞增殖和肿瘤生长。综上所述，我们证明NIR通过抑制RB乙酰化和促进RB降解来部分促进CRC进展。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。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，NIR的下调可能有助于维持DNA损伤下的细胞稳态。因此，NIR的消耗会抑制小鼠异种移植物中的细胞增殖和肿瘤生长。综上所述，我们证明NIR通过抑制RB乙酰化和促进RB降解来部分促进CRC进展。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。NIR的耗尽会抑制小鼠异种移植物中的细胞增殖和肿瘤生长。综上所述，我们证明NIR通过抑制RB乙酰化和促进RB降解来部分促进CRC进展。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。NIR的耗尽会抑制小鼠异种移植物中的细胞增殖和肿瘤生长。综上所述，我们证明NIR通过抑制RB乙酰化和促进RB降解来部分促进CRC进展。靶向NIR可能为NIR上调的CRC患者提供潜在的治疗策略。