Usp44, a member of the ubiquitin-specific proteases (USPs) family, functions as a deubiquitinase. It participates in multiple biological processes by regulating the deubiquitination of various substrates, which is crucial for maintaining normal cellular functions and is associated with pathways like DNA repair, epigenetic regulation, and immune response [5].

In nasopharyngeal carcinoma (NPC), Usp44 is hypermethylated, leading to its down-regulation. It enhances NPC cells' sensitivity to radiotherapy by recruiting and stabilizing the E3 ubiquitin ligase TRIM25, which facilitates Ku80 degradation and inhibits non-homologous end-joining DNA repair. Knockout of TRIM25 reverses the radiotherapy sensitization effect of Usp44 [1]. In neuroblastoma, high levels of Usp44 are associated with aggressive features. Depletion of the histone H2B ubiquitin ligase subunit RNF20, a related factor, led to similar findings as Usp44 manipulation, suggesting histone H2B as a target of Usp44 activity [2]. In regulatory T cells (Tregs), Usp44 stabilizes the transcription factor FOXP3 by removing K48-linked ubiquitin modifications. Tregs lacking Usp44 are less effective in vitro and in vivo in inflammatory disease and cancer models [3]. In hepatocellular carcinoma (HCC), Usp44 suppresses tumor progression by inhibiting the Hedgehog signaling pathway and PDL1 expression [4]. In thyroid cancer, Usp44 inactivation accelerates tumor progression by inducing ubiquitylation and degradation of p21 [6]. In oral squamous cell carcinoma (OSCC), overexpression of Usp44 inhibits tumor growth and metastasis by stabilizing HEXIM1 protein [7]. In breast cancer, Usp44 hypermethylation promotes cell proliferation and metastasis, while its overexpression suppresses these cancer cell behaviors [8].

In summary, Usp44 plays diverse and significant roles in multiple biological processes and diseases. Gene knockout or knockdown models in these studies have revealed its functions in tumorigenesis, DNA repair, immune regulation, etc. These findings suggest that Usp44 could be a potential therapeutic target for various cancers, providing new insights into disease mechanisms and treatment strategies.

References:

1. Chen, Yang, Zhao, Yin, Yang, Xiaojing, Ma, Jun, Liu, Na. 2022. USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma. In Nature communications, 13, 501. doi:10.1038/s41467-022-28158-2. https://pubmed.ncbi.nlm.nih.gov/35079021/

2. Ekstrom, Thomas L, Hussain, Sajjad, Bedekovics, Tibor, Johnsen, Steven A, Galardy, Paul J. . USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming. In Molecular cancer research : MCR, 22, 812-825. doi:10.1158/1541-7786.MCR-23-0454. https://pubmed.ncbi.nlm.nih.gov/38775808/

3. Yang, Jing, Wei, Ping, Barbi, Joseph, Pan, Fan, Li, Bin. 2020. The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation. In EMBO reports, 21, e50308. doi:10.15252/embr.202050308. https://pubmed.ncbi.nlm.nih.gov/32644293/

4. Chen, Sisi, Zhou, Binghai, Huang, Wei, Wang, Wei, Xie, Peiyi. 2023. The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression. In Cell death & disease, 14, 830. doi:10.1038/s41419-023-06358-y. https://pubmed.ncbi.nlm.nih.gov/38097536/

5. Lou, Yuming, Ye, Minfeng, Xu, Chaoyang, Tao, Feng. 2022. Insight into the physiological and pathological roles of USP44, a potential tumor target (Review). In Oncology letters, 24, 455. doi:10.3892/ol.2022.13575. https://pubmed.ncbi.nlm.nih.gov/36380875/

6. Liu, Yan, Yuan, Mengmeng, Xu, Xinxin, Yu, Wei, Ji, Meiju. 2024. USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21. In International journal of biological sciences, 20, 5223-5238. doi:10.7150/ijbs.99817. https://pubmed.ncbi.nlm.nih.gov/39430240/

7. Chen, Shuai, Wu, Kefan, Zong, Yingrui, Deng, Zhifen, Xia, Zongping. 2024. USP44 regulates HEXIM1 stability to inhibit tumorigenesis and metastasis of oral squamous cell carcinoma. In Biology direct, 19, 143. doi:10.1186/s13062-024-00573-z. https://pubmed.ncbi.nlm.nih.gov/39722007/

8. Chen, Xin, Wu, Xiaotang, Lei, Wen. 2020. USP44 hypermethylation promotes cell proliferation and metastasis in breast cancer. In Future oncology (London, England), 17, 279-289. doi:10.2217/fon-2020-0415. https://pubmed.ncbi.nlm.nih.gov/32956592/