Uap1l1, or Uridine diphosphate-N-acetylglucosamine pyrophosphorylase-1-like-1, shows approximately 59% sequence identity to UAP1 and is involved in protein glycosylation, specifically in the synthesis of the sugar donor (UDP-GlcNac) for N-acetylglucosamine modification (O-GlcNAcylation) of proteins, although it has limited UDP-GlcNAc synthesis activity. It directly interacts with OGT, potentially modulating OGT-mediated protein O-GlcNAcylation, and is thus important for various biological processes [5].

In multiple cancer types, loss-of-function experiments have revealed its oncogenic role. In glioma, knockdown of Uap1l1 in cell lines U251 and U87 suppressed cell proliferation and increased apoptosis both in vitro and in an in vivo subcutaneous xenograft model, with higher Uap1l1 expression associated with higher tumor grades and poorer prognoses [1]. Similar results were seen in prostate cancer, where Uap1l1 promoted cell proliferation, migration, and invasion, and this was inhibited by downregulating its downstream gene CDCA8 [2]. In esophageal squamous cell carcinoma, knockdown of Uap1l1 hindered cell proliferation, migration, and enhanced apoptosis in vitro, and inhibited tumor development in an in vivo xenograft model, while also regulating apoptosis-related proteins and affecting the PI3K/Akt, CCND1, and MAPK pathways [3]. In gastric cancer, Uap1l1 promoted tumor development through regulating cell proliferation, colony formation, apoptosis, and migration, and its effect was related to the regulation of CDK6 [4]. In human hepatoma cells, Uap1l1 knockdown reduced cell proliferation both in vitro and in vivo [5]. Additionally, Uap1l1 may be a potential marker of temozolomide resistance in glioblastoma [6].

In conclusion, Uap1l1 plays a crucial role in promoting tumor cell proliferation, migration, and invasion, while inhibiting apoptosis in multiple cancer types, as demonstrated by loss-of-function experiments. These findings highlight its potential as a therapeutic target in cancer treatment, with research on Uap1l1 contributing to a better understanding of cancer development mechanisms.

References:

1. Yang, Zhuanyi, Yang, Zhiquan, Hu, Zhongliang, Wang, Ying, Feng, Deyun. . UAP1L1 plays an oncogene-like role in glioma through promoting proliferation and inhibiting apoptosis. In Annals of translational medicine, 9, 542. doi:10.21037/atm-20-2809. https://pubmed.ncbi.nlm.nih.gov/33987240/

2. Wu, Xing-Cheng, Yu, Yu-Zhong, Zuo, Yu-Zhi, Yan, Wei-Gang, Zhao, Shan-Chao. 2022. Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity. In Journal of translational medicine, 20, 91. doi:10.1186/s12967-022-03291-0. https://pubmed.ncbi.nlm.nih.gov/35168617/

3. Xiao, Xiaoxiong, Jiang, Lei, Hu, Huoli, Jiao, Yang, Wei, Guangxia. 2021. Silencing of UAP1L1 inhibits proliferation and induces apoptosis in esophageal squamous cell carcinoma. In Molecular carcinogenesis, 60, 179-187. doi:10.1002/mc.23278. https://pubmed.ncbi.nlm.nih.gov/33434300/

4. Qi, Jing, Liu, Sheng, Liu, Weihang, Cai, Gaoqiang, Liao, Guoqing. 2020. Identification of UAP1L1 as tumor promotor in gastric cancer through regulation of CDK6. In Aging, 12, 6904-6927. doi:10.18632/aging.103050. https://pubmed.ncbi.nlm.nih.gov/32310823/

5. Lai, Ching-Yu, Liu, Hsuan, Tin, Kai Xuan, Yen, Jeffrey Jong-Young, Yang-Yen, Hsin-Fang. 2018. Identification of UAP1L1 as a critical factor for protein O-GlcNAcylation and cell proliferation in human hepatoma cells. In Oncogene, 38, 317-331. doi:10.1038/s41388-018-0442-6. https://pubmed.ncbi.nlm.nih.gov/30097606/

6. Li, Da, Yan, Jun, Li, Kang, Liu, Xiaohua, Xi, Zhuge. 2023. Identification of potential glioma drug resistance target proteins based on ultra-performance liquid chromatography-mass spectrometry differential proteomics. In PeerJ, 11, e16426. doi:10.7717/peerj.16426. https://pubmed.ncbi.nlm.nih.gov/38054015/