HNMT Promotes the Occurrence and Progression of Nasopharyngeal Carcinoma by Inhibiting the IFN/TXNIP/p53 Axis

Abstract

Objective

Histamine N-methyltransferase (HNMT) is involved primarily in histamine metabolism, but emerging evidence suggests its potential role in cancer progression. This study investigated the role of HNMT in nasopharyngeal carcinoma (NPC) and its impact on interferon (IFN) signaling, thioredoxin-interacting protein (TXNIP), and p53 tumor suppressor pathways.

Methods

HNMT expression in NPC tissues and cell lines was analyzed via qPCR and Western blotting. Functional assays, including cell proliferation, migration, invasion, and apoptosis, were performed after HNMT knockdown or overexpression. Transcriptomic sequencing was used to identify differentially expressed genes (DEGs). In addition, we examined the relationship between HNMT and the IFN/TXNIP/p53 axis via rescue experiments in vitro and in vivo models via qPCR and Western blotting.

Results

HNMT knockdown reduced cell proliferation, migration, and invasion, and promoted apoptosis in NPC tissues and cell lines. TXNIP was the most significantly upregulated gene following HNMT knockdown. Inhibition of the IFN pathway reversed these effects, confirming the role of HNMT in downregulating the IFN/TXNIP/p53 pathway. An in vivo study revealed that HNMT overexpression correlated with reduced expression of TXNIP and p53 in NCG mice.

Conclusion

In NPC, HNMT promotes tumor growth and progression by inhibiting the IFN/TXNIP/p53 axis. These findings suggest that targeting the HNMT axis or restoring its function could provide new therapeutic strategies for NPC.

Keywords

Nasopharyngeal carcinoma / Histamine N-methyltransferase / Tumor growth / IFN/TXNIP/p53 axis / RNA sequencing

References

[1] ChenYP, ChanAT, LeQT, et al.. Nasopharyngeal carcinoma. Lancet., 2019, 394(10192): 64-80.

[2] NgWT, ChowJC, BeitlerJJ, et al.. Current radiotherapy considerations for nasopharyngeal carcinoma. Cancers., 2022, 14235773.

[3] WongKC, HuiEP, LoKW, et al.. Nasopharyngeal carcinoma: an evolving paradigm. Nat Rev Clin Oncol, 2021, 18(11): 679-695.

[4] HuangH, YaoY, DengX, et al.. Immunotherapy for nasopharyngeal carcinoma: Current status and prospects (Review). Int J Oncol., 2023, 63297.

[5] LooiCK, FoongLC, ChungFFL, et al.. Targeting the crosstalk of epigenetic modifications and immune evasion in nasopharyngeal cancer. Cell Biol Toxicol., 2023, 39(6): 2501-2526.

[6] MoY, WangY, ZhangS, et al.. Circular RNA circRNF13 inhibits proliferation and metastasis of nasopharyngeal carcinoma via SUMO2. Mol Cancer., 2021, 201112.

[7] JiangJ, YingH. Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment. J Exp Clin Cancer Res., 2022, 411244.

[8] WuQ, YuX, LiJ, et al.. Metabolic regulation in the immune response to cancer. Cancer Commun., 2021, 41(8): 661-694.

[9] QinX, YangC, XuH, et al.. Cell‐derived biogenetic gold nanoparticles for sensitizing radiotherapy and boosting immune response against cancer. Small., 2021, 17502103984.

[10] ReinerD, SeifertL, DeckC, et al.. Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H3 receptor for Prader–willi syndrome. Sci Rep., 2020, 10113558.

[11] McClainJL, Morales-SotoW, GonzalesJ, et al.. Sexually dimorphic effects of histamine degradation by enteric glial histamine N-methyltransferase (HNMT) on visceral hypersensitivity. Biomolecules., 2023, 13111651.

[12] O’MahonyL, AkdisM, AkdisCA. Regulation of the immune response and inflammation by histamine and histamine receptors. J Allergy Clin Immunol., 2011, 128(6): 1153-1162.

[13] PietrangeliP, SeguellaL, AnnunziataG, et al.. Lathyrus sativus diamine oxidase counteracts histamine-induced cell proliferation, migration and pro-angiogenic mediators release in human colon adenocarcinoma cell line Caco-2. Phytother Res., 2019, 33(7): 1878-1887.

[14] KimKH, ParkJ, ChoY, et al.. Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach. Cell Mol Gastroenterol Hepatol., 2023, 15(1): 213-236.

[15] KuoKT, LinCH, WangCH, et al.. HNMT upregulation induces cancer stem cell formation and confers protection against oxidative stress through interaction with HER2 in non-small cell lung cancer. Int J Mol Sci., 2022, 2331663.

[16] FujitaY, MatsuokaH, ChibaY, et al.. Novel single-nucleotide polymorphism biomarkers to predict opioid effects for cancer pain. Oncol Lett., 2023, 262355.

[17] LüthS, SchraderJ, ZanderS, et al.. Chronic inflammatory IFN-γ signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis. Cancer Res., 2011, 71(11): 3763-3771.

[18] DengJ, PanT, LiuZ, et al.. The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control. Br J Cancer., 2023, 129(12): 1877-1892.

[19] LasfarA, GogasH, ZlozaA, et al.. IFN-λ cancer immunotherapy: new kid on the block. Immunotherapy., 2016, 8(8): 877-888.

[20] WuW, ZhangZ, JingD, et al.. SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma. Cell Death Dis., 2022, 136523.

[21] RenD, QinG, ZhaoJ, et al.. Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer. Am J Cancer Res., 2020, 10(9): 2851-2864

[22] ZhangCR, OstranderEL, KukharO, et al.. Txnip enhances fitness of Dnmt3a-mutant hematopoietic stem cells via p21. Blood Cancer Disc., 2022, 3(3): 220-239.

[23] FengL, DingR, QuX, et al.. BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP. Cell Death Dis., 2023, 144287.

[24] ChanA, TeoP, JohnsonP. Nasopharyngeal carcinoma. Ann Oncol., 2002, 13(7): 1007-1015.

[25] LianL, LeZ, WangZ, et al.. SIRT1 Inhibits High Glucose-Induced TXNIP/NLRP3 Inflammasome Activation and Cataract Formation. Invest Ophthalmol Vis Sci., 2023, 64316.

[26] HafnerA, BulykML, JambhekarA, et al.. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol., 2019, 20(4): 199-210.

[27] Rodriguez-PastranaI, BirliE, CouttsAS. p53-dependent DNA repair during the DNA damage response requires actin nucleation by JMY. Cell Death Differ., 2023, 30(7): 1636-1647.

[28] YuG, LuoH, ZhangN, et al.. Loss of p53 sensitizes cells to palmitic acid-induced apoptosis by reactive oxygen species accumulation. Int J Mol Sci., 2019, 20246268.

[29] ShethS, BodnarJ, GhazalpourA, et al.. Hepatocellular carcinoma in Txnip-deficient mice. Oncogene., 2006, 25(25): 3528-3536.

[30] LiY, DengW, WuJ, et al.. TXNIP exacerbates the senescence and aging-related dysfunction of β cells by inducing cell cycle arrest through p38–p16/p21-CDK-Rb pathway. Antioxid Redox Signal., 2023, 38(7–9): 480-495.

[31] AlspachE, LussierDM, SchreiberRD. Interferon γ and its important roles in promoting and inhibiting spontaneous and therapeutic cancer immunity. Cold Spring Harb Perspect Biol., 2019, 113. a028480

[32] QinZ, LiuH, ShengQ, et al.. Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS–STING signaling in mice. Eur J Immunol., 2023, 5392250211.

[33] GervaisA, Le Floc'hC, Le VoyerT, et al.. A sensitive assay for measuring whole-blood responses to type I IFNs. Proc Natl Acad Sci U S A., 2024, 12140. e2402983121

[34] SuhHW, YunS, SongH, et al.. TXNIP interacts with hEcd to increase p53 stability and activity. Biochem Biophys Res Commun., 2013, 438(2): 264-269.

[35] JungH, KimMJ, KimDO, et al.. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab., 2013, 18(1): 75-85.

[36] Yee-LinV, Pooi-FongW, Soo-BengAK. Nutlin-3, A p53-Mdm2 antagonist for nasopharyngeal carcinoma treatment. Mini Rev Med Chem., 2018, 18(2): 173-183.

[37] XiaW, JiangP. p53 promotes antiviral innate immunity by driving hexosamine metabolism. Cell Rep., 2024, 432. 113724

[38] ParkHS, SongJW, ParkJH, et al.. TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation. Autophagy., 2021, 17(9): 2549-2564.

Funding

Science Research Foundation of Yunnan Education Bureau(2023Y0631)

Yunnan Provincial Science and Technology Project(202303AP140005)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to Huazhong University of Science and Technology