Abstract
Aim
Histamine decarboxylase (HDC) catalyzes decarboxylation of histidine to generate histamine. This enzyme affects several biological processes including inflammation, allergy, asthma, and cancer, although the underlying mechanism is not fully understood. The present study provides a novel insight into the relationship between the transcription factor FLI1 and its downstream target HDC, and their effects on inflammation and leukemia progression.
Methods
Promoter analysis combined with chromatin immunoprecipitation (ChIp) was used to demonstrate binding of FLI1 to the promoter of HDC in leukemic cells. Western blotting and RT-qPCR were used to determine expression of HDC and allergy response genes, and lentivirus shRNA was used to knock-down target genes. Proliferation, cell cycle, apoptosis assays and molecular docking were used to determine the effect of HDC inhibitors in culture. An animal model of leukemia was employed to test the effect of HDC inhibitory compounds in vivo.
Results
Results presented herein demonstrate that FLI1 transcriptionally regulates HDC by direct binding to its promoter. Using genetic and pharmacological inhibition of HDC, or the addition of histamine, the enzymatic product of HDC, we show neither have a discernable effect on leukemic cell proliferation in culture. However, HDC controls several inflammatory genes including IL1B and CXCR2 that may influence leukemia progression in vivo through the tumor microenvironment. Indeed, diacerein, an IL1B inhibitor, strongly blocked Fli-1-induced leukemia in mice. In addition to allergy, FLI1 is shown to regulate genes associated with asthma such as IL1B, CPA3 and CXCR2. Toward treatment of these inflammatory conditions, epigallocatechin (EGC), a tea polyphenolic compound, is found strongly inhibit HDC independently of FLI1 and its downstream effector GATA2. Moreover, the HDC inhibitor, tetrandrine, suppressed HDC transcription by directly binding to and inhibiting the FLI1 DNA binding domain, and like other FLI1 inhibitors, tetrandrine strongly suppressed cell proliferation in culture and leukemia progression in vivo.
Conclusion
These results suggest a role for the transcription factor FLI1 in inflammation signaling and leukemia progression through HDC and point to the HDC pathway as potential therapeutics for FLI1-driven leukemia.
Abbreviation
HDC, Histamine decarboxylase; EGC, epigallocatechin; TS, Tourette syndrome; IMC’s, immature myeloid cells; F-MuLV, Friend Murine Leukemia virus; FBS, FLI1 binding site; EGCG, Epigallocatechin gallate; CLC, Charcot-Leyden crystal galectin; CPA3, carboxypeptidase 3; DNASE1L3, deoxyribonuclease 1-like 3; liver/bone/kidnalkaline phosphatase, ALPLey; CXCR2, C-X-C motif chemokine receptor 2; IL1B, interleukin 1B; Tet, Tetrandrine; Fam, Famotidine; His, Histamine.
Data Sharing Statement
All data generated or analyzed during this study are included in this article.
Ethical Approval
The animal study was carried out in accordance with the ARRIVE guidline.Citation36 Animal care and experimental procedures were conducted with the accredited animal ethics committee of the Guizhou Medical University and Council of Animal Care (Approval ID #1900373). The animal welfare guidelines were then carried out according to Institutional Animal Care and Use Committee guidelines of Guizhou Medical University.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflict of interest.