NIR promotes progression of colorectal cancer through regulating RB.
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.
['Li|Yuan|Y|', 'Wang|Ling|L|', 'Liu|Xiaofeng|X|', 'Zhang|Chunfeng|C|', 'Du|Xiaojuan|X|', 'Xing|Baocai|B|']
D000107:Acetylation D000368:Aged D000818:Animals D063646:Carcinogenesis D045744:Cell Line, Tumor D049109:Cell Proliferation D015179:Colorectal Neoplasms D004249:DNA Damage D005260:Female D015972:Gene Expression Regulation, Neoplastic D064593:Heterografts D006801:Humans D008297:Male D051379:Mice D008875:Middle Aged D059748:Proteolysis D034741:RNA, Small Interfering D012097:Repressor Proteins D016160:Retinoblastoma Protein D016159:Tumor Suppressor Protein p53 D054875:Ubiquitination
NIR Colorectal cancer RB RB acetylation Protein degradation