Hnmt, or histamine N-methyltransferase, is an enzyme crucial for histamine metabolism. Histamine is involved in numerous biological functions such as allergic responses, gastric acid secretion regulation, and acting as a neurotransmitter in the central nervous system. Hnmt terminates histamine's local action primarily through methylation [2].

In non-small-cell lung cancer (NSCLC), Hnmt is significantly upregulated, co-expressed with HER2, and confers a worse prognosis. Depletion of Hnmt using shRNA decreased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression, while overexpression had the opposite effects. Also, Hnmt was found to directly interact with HER2, and its upregulation may increase tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties [1].

In the enteric nervous system, glial Hnmt contributes to histamine clearance. Deleting Hnmt in Sox10+ enteric glia using CRISPR-Cas9 increased glial histamine levels and altered visceromotor responses to colorectal distension in male mice, protecting them from histamine-driven visceral hypersensitivity, with no effect in females [3].

In the central nervous system, Hnmt-deficient mice showed a robust increase in brain histamine concentration, demonstrating the essential role of Hnmt in the brain histamine system. Clinical studies have associated single nucleotide polymorphisms of the human Hnmt gene with several brain disorders like Parkinson's disease [4].

In summary, Hnmt plays a vital role in histamine metabolism across different biological systems. Studies using gene knockout or conditional knockout models in mice have revealed its significance in diseases such as NSCLC, visceral hypersensitivity, and brain disorders. Understanding Hnmt's functions can potentially lead to new therapeutic strategies for these diseases [1,3,4].

References:

1. Kuo, Kuang-Tai, Lin, Cheng-Hsin, Wang, Chun-Hua, Lee, Wei-Hwa, Huang, Wen-Chien. 2022. HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer. In International journal of molecular sciences, 23, . doi:10.3390/ijms23031663. https://pubmed.ncbi.nlm.nih.gov/35163585/

2. Horton, J R, Sawada, K, Nishibori, M, Zhang, X, Cheng, X. . Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. In Structure (London, England : 1993), 9, 837-49. doi:. https://pubmed.ncbi.nlm.nih.gov/11566133/

3. McClain, Jonathon L, Morales-Soto, Wilmarie, Gonzales, Jacques, Demireva, Elena Y, Gulbransen, Brian D. 2023. Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity. In Biomolecules, 13, . doi:10.3390/biom13111651. https://pubmed.ncbi.nlm.nih.gov/38002333/

4. Yoshikawa, Takeo, Nakamura, Tadaho, Yanai, Kazuhiko. 2019. Histamine N-Methyltransferase in the Brain. In International journal of molecular sciences, 20, . doi:10.3390/ijms20030737. https://pubmed.ncbi.nlm.nih.gov/30744146/