NONO, also known as non-POU domain-containing octamer-binding protein or p54nrb, belongs to the Drosophila behaviour/human splicing (DBHS) family. It is a multifunctional nuclear protein that acts as a “molecular scaffold” in gene regulation. NONO is involved in almost every step of gene regulation, such as mRNA splicing, DNA unwinding, transcriptional regulation, nuclear retention of defective RNA, and DNA repair. It participates in numerous biological processes including cell proliferation, apoptosis, migration, and DNA damage repair [1,5].

In vascular calcification, smooth muscle-specific NONO-knockout mice showed increased susceptibility to vascular calcification, indicating that NONO is a negative regulator of this process, likely by inhibiting bone morphogenetic protein 2 (BMP2) transcription [3]. In B-cell development, global deletion of NONO in mice impaired early B-cell development at the pro-to pre-B-cell transition stage and B-cell maturation in the spleen, while NONO-deficient B cells had abnormal B-cell receptor (BCR)-induced apoptosis and altered BCR-induced gene expression [4]. In glioblastoma multiforme (GBM), knockdown of NONO suppressed GBM growth, and a small molecule inhibitor of NONO, Auranofin, suppressed GBM tumor growth in an orthotopic xenograft model in mice, suggesting NONO as a potential therapeutic target for GBM [2].

In conclusion, NONO is a crucial regulator in multiple biological processes. Model-based research, especially using NONO knockout mouse models, has revealed its significance in diseases like vascular calcification, B-cell-related disorders, and GBM. These findings suggest that targeting NONO could be a promising strategy for treating related diseases.

References:

1. Feng, Peifu, Li, Ling, Deng, Tanggang, Zhang, Lei, Ye, Mao. 2020. NONO and tumorigenesis: More than splicing. In Journal of cellular and molecular medicine, 24, 4368-4376. doi:10.1111/jcmm.15141. https://pubmed.ncbi.nlm.nih.gov/32168434/

2. Wang, Xu, Han, Mingzhi, Wang, Shuai, Li, Xingang, Wang, Jian. 2022. Targeting the splicing factor NONO inhibits GBM progression through GPX1 intron retention. In Theranostics, 12, 5451-5469. doi:10.7150/thno.72248. https://pubmed.ncbi.nlm.nih.gov/35910786/

3. Lu, Yue, Meng, Linlin, Ren, Ruiqing, Zhang, Yun, Zhang, Cheng. 2024. Paraspeckle protein NONO attenuates vascular calcification by inhibiting bone morphogenetic protein 2 transcription. In Kidney international, 105, 1221-1238. doi:10.1016/j.kint.2024.01.039. https://pubmed.ncbi.nlm.nih.gov/38417578/

4. Zhang, Yongguang, Cui, Dongya, Huang, Miaohui, Chen, Liling, Chen, Qi. . NONO regulates B-cell development and B-cell receptor signaling. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e22862. doi:10.1096/fj.202201909RR. https://pubmed.ncbi.nlm.nih.gov/36906291/

5. Ronchetti, Domenica, Traini, Valentina, Silvestris, Ilaria, Bolli, Niccolò, Taiana, Elisa. 2024. The pleiotropic nature of NONO, a master regulator of essential biological pathways in cancers. In Cancer gene therapy, 31, 984-994. doi:10.1038/s41417-024-00763-x. https://pubmed.ncbi.nlm.nih.gov/38493226/