Otud6a, an ovarian tumor deubiquitinase, is a deubiquitinating enzyme that plays crucial roles in multiple biological processes. It is involved in pathways related to cell proliferation, innate immune response, and inflammation [1,3,6]. Deubiquitination is a key post-translational modification regulated by Otud6a, which impacts protein stability and function, thus being of great biological importance. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying Otud6a's functions.

In KO mouse models, Otud6a deficiency attenuated DSS or TNBS-induced colitis, as well as AOM/DSS-induced colitis-related colon cancer, indicating its role in promoting intestinal inflammation and colitis by enhancing NLRP3 inflammasome activation [1]. In BBN-induced conditional Otud6a knockout mouse models, CKO mice were less prone to BCa tumorigenesis, suggesting that Otud6a promotes tumour progression and chemoresistance by deubiquitinating and stabilizing CDC6 [2]. In the context of prostate cancer, genetic ablation of Otud6a in Hi-Myc transgenic PrCa mice repressed prostatic tumorigenesis, demonstrating its role in promoting prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc [4]. In addition, OTUD6A oligonucleotides suppressed prostate tumorigenesis in PtenPC-/-mice and patient-derived xenograft (PDX) models, as OTUD6A deubiquitinates and stabilizes Brg1 and AR [5]. In OTUD6a gene knockout mice, transverse aortic constriction (TAC)-or angiotensin II (Ang II)-induced ventricular hypertrophy and dysfunction were attenuated, showing its role in driving cardiac inflammation and hypertrophy by deubiquitination of STING [7]. Knockout of Otud6A in xenografted nude mice inhibited tumor growth, suggesting its role in promoting breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy [8]. The depletion of OTUD6A in human colorectal cancer cells led to suppressed mitochondrial fission and less tumorigenesis, indicating its role in promoting cancer cell proliferation via regulating Drp1 stability and mitochondrial fission [9].

In conclusion, Otud6a, through its deubiquitination function, is involved in various biological processes and diseases. The use of KO and CKO mouse models has revealed its significant roles in intestinal inflammation, various cancers, and cardiac hypertrophy. These findings suggest that Otud6a could potentially be a therapeutic target for treating related diseases.

References:

1. Liu, Xin, Fang, Yi, Lv, Xinting, Liang, Guang, Wang, Yi. 2023. Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3. In Cell death and differentiation, 30, 1457-1471. doi:10.1038/s41418-023-01148-7. https://pubmed.ncbi.nlm.nih.gov/36932155/

2. Cui, Jianfeng, Liu, Xiaochen, Shang, Qinghong, Shi, Benkang, Zou, Yongxin. 2024. Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance. In Molecular cancer, 23, 86. doi:10.1186/s12943-024-01996-y. https://pubmed.ncbi.nlm.nih.gov/38685067/

3. Li, Zhiwei, Li, Guanwen, Li, Yunfei, Wu, Chen, You, Fuping. 2023. Deubiquitinase OTUD6A Regulates Innate Immune Response via Targeting UBC13. In Viruses, 15, . doi:10.3390/v15081761. https://pubmed.ncbi.nlm.nih.gov/37632103/

4. Peng, Yunhua, Liu, Jing, Wang, Zhen, Liu, Jiankang, Long, Jiangang. 2022. Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc. In Cell death and differentiation, 29, 1730-1743. doi:10.1038/s41418-022-00960-x. https://pubmed.ncbi.nlm.nih.gov/35217790/

5. Fu, Xuhong, Zhao, Junjie, Yu, Guopeng, Xu, Bin, Huang, Liyu. 2022. OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR. In Communications biology, 5, 182. doi:10.1038/s42003-022-03133-1. https://pubmed.ncbi.nlm.nih.gov/35233061/

6. Kim, Hyo Jin, Kim, Jongchan. 2021. OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase. In International journal of molecular sciences, 22, . doi:10.3390/ijms22041936. https://pubmed.ncbi.nlm.nih.gov/33669244/

7. Fang, Zimin, Han, Jibo, Lin, Liming, Huang, Zhouqing, Liang, Guang. 2024. Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167061. doi:10.1016/j.bbadis.2024.167061. https://pubmed.ncbi.nlm.nih.gov/38342418/

8. Zhao, Yan, Huang, Xinping, Zhu, Dan, Tian, Yonglu, Zheng, Xiaofeng. 2022. Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy. In Cell death and differentiation, 29, 2531-2544. doi:10.1038/s41418-022-01036-6. https://pubmed.ncbi.nlm.nih.gov/35768646/

9. Shi, Le, Liu, Jing, Peng, Yunhua, Liu, Jiankang, Long, Jiangang. 2020. Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission. In Molecular oncology, 14, 3169-3183. doi:10.1002/1878-0261.12825. https://pubmed.ncbi.nlm.nih.gov/33070427/