Nit2, also known as nitrilase family member 2 or ω-amidase, is involved in multiple biological processes. It can catalyze the hydrolysis of α-ketoglutaramate to α-ketoglutarate and ammonia, and also acts on other substrates like α-ketosuccinamate and succinamate [3,6]. In Neurospora crassa, NIT2 is a global transcription factor regulating nitrogen metabolism-related genes, and in Chlamydomonas reinhardtii, it is crucial for nitrate signaling in the nitrate-assimilation pathway [4,7,9].

In cancer research, depletion or low expression of NIT2 led to 5-Fluorouracil (5-FU) resistance in gastric cancer cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, NIT2 interacts with bromodomain-containing protein 1 (BRD1) to inhibit histone H3 acetylation and oxidative phosphorylation (OXPHOS) gene expression. Upon 5-FU stimulation, NIT2 phosphorylation causes its autophagic degradation, resulting in BRD1 phase separation and increased OXPHOS [1]. In tongue squamous cell carcinoma (TSCC), NIT2 is overexpressed and its positive expression is associated with decreased disease-free survival rate and overall survival [2]. In lung adenocarcinoma, the T allele of rs277646 in NIT2 is associated with an increased risk, higher NIT2 expression, and affects 3'UTR transcript length and miRNA binding [5]. Ectopic expression of Nit2 in HeLa cells inhibits cell growth through G(2) arrest [8].

In conclusion, Nit2 has diverse functions from metabolism-related enzyme activity to transcriptional regulation in nitrogen metabolism and nitrate signaling. In cancer, its role in chemoresistance, prognosis, and cell growth regulation has been revealed. These findings from various in vitro and in vivo models contribute to understanding its role in disease, especially in cancer, and may provide potential therapeutic targets.

References:

1. Wang, Ziyang, Di, Yuqin, Wen, Xiangqiong, Wang, Xiongjun, He, Weiling. 2024. NIT2 dampens BRD1 phase separation and restrains oxidative phosphorylation to enhance chemosensitivity in gastric cancer. In Science translational medicine, 16, eado8333. doi:10.1126/scitranslmed.ado8333. https://pubmed.ncbi.nlm.nih.gov/39565874/

2. Chen, Shan, Wang, Zengyan, Feng, Chongjin. 2020. NIT2 overexpression predicts poor prognosis in tongue squamous cell carcinoma patients. In Molecular biology reports, 47, 1553-1561. doi:10.1007/s11033-019-05197-5. https://pubmed.ncbi.nlm.nih.gov/31925645/

3. Epova, Ekaterina Yu, Shevelev, Alexei B, Shurubor, Yevgeniya I, Lebedeva, Anna A, Krasnikov, Boris F. 2021. A novel efficient producer of human ω-amidase (Nit2) in Escherichia coli. In Analytical biochemistry, 632, 114332. doi:10.1016/j.ab.2021.114332. https://pubmed.ncbi.nlm.nih.gov/34391728/

4. Tao, Y, Marzluf, G A. . The NIT2 nitrogen regulatory protein of Neurospora: expression and stability of nit-2 mRNA and protein. In Current genetics, 36, 153-8. doi:. https://pubmed.ncbi.nlm.nih.gov/10501938/

5. Xu, Huiwen, Wu, Yutong, Chen, Qiong, Cui, Jiahua, Chu, Minjie. 2024. Integrating apaQTL and eQTL analysis identifies a potential causal variant associated with lung adenocarcinoma risk in the Chinese population. In Communications biology, 7, 860. doi:10.1038/s42003-024-06502-0. https://pubmed.ncbi.nlm.nih.gov/39003419/

6. Silva Teixeira, Carla S, Sousa, Sérgio F, Cerqueira, Nuno M F S A. 2021. An Unsual Cys-Glu-Lys Catalytic Triad is Responsible for the Catalytic Mechanism of the Nitrilase Superfamily: A QM/MM Study on Nit2. In Chemphyschem : a European journal of chemical physics and physical chemistry, 22, 796-804. doi:10.1002/cphc.202000751. https://pubmed.ncbi.nlm.nih.gov/33463886/

7. Camargo, Antonio, Llamas, Angel, Schnell, Rogene A, Fernández, Emilio, Galván, Aurora. 2007. Nitrate signaling by the regulatory gene NIT2 in Chlamydomonas. In The Plant cell, 19, 3491-503. doi:. https://pubmed.ncbi.nlm.nih.gov/18024571/

8. Lin, Chun-Hung, Chung, Ming-Yi, Chen, Wen-Bin, Chien, Chin-Hsiang. 2007. Growth inhibitory effect of the human NIT2 gene and its allelic imbalance in cancers. In The FEBS journal, 274, 2946-56. doi:. https://pubmed.ncbi.nlm.nih.gov/17488281/

9. Schnell, R A, Lefebvre, P A. . Isolation of the Chlamydomonas regulatory gene NIT2 by transposon tagging. In Genetics, 134, 737-47. doi:. https://pubmed.ncbi.nlm.nih.gov/8394263/