Horita, Y. | Search bioRxiv

bioRxiv2023

Ikzf1 association with Foxp3 for Foxp3-dependent gene repression in Treg cells: induction of autoimmunity and tumor immunity by disrupting the association

The transcription factor Foxp3 specifically expressed in regulatory T (Treg) cells controls Treg function by repressing some genes and activating others. We have shown here that the transcription factor Ikzf1 associates with Foxp3 via its exon 5 (called IkE5) and that conditional deletion of IkE5 up-regulated the genes, including Ifng, normally repressed by Foxp3 upon TCR stimulation. IkE5-deletion in Treg cells indeed incurred IFN-{gamma} overproduction, which destabilized Foxp3 expression and impaired suppressive function, consequently producing fatal systemic autoimmune diseases and evoking strong anti-tumor immunity. In addition, pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-{gamma} overproduction in human Treg cells. Mechanistically, the Foxp3/Ikzf1/Ikzf3 complex exerted gene-repressing function by competing with epigenetic co-activators, such as p300 and NFAT1, for binding to the target gene loci via chromatin remodeling. Collectively, the association of Ikzf1 with Foxp3 is essential for repressive function of Foxp3, and can be targeted to control autoimmunity and tumor immunity.

immunology↗

bioRxiv2022

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer

BackgroundFluoropyrimidine-based adjuvant chemotherapy is globally recommended for postoperative stage III colon cancer and high-risk stage II patients. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, a recurrence-prevention biomarker of adjuvant chemotherapy for colorectal cancer is necessary for providing such treatments to appropriate patients. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between the single-nucleotide variants of autophagy-related genes and recurrence rates to identify the recurrence-prevention biomarkers of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer patient relapse rates. ResultsWe detected 560 single-nucleotide variants or insertions/deletions in the target region. The results of Fishers exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single- nucleotide variants (c.1018G>A [p < 0.005] or c.1562A>C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. ConclusionsThe two single-nucleotide variants of this mitophagy-related gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

cancer biology↗