Biology subjects

Arnaiz, E.

Publications and source records attributed to Arnaiz, E..

3 recordsLinked to original sources

bioRxiv2025

SET1B drives sustained HIF activity and disease progression in clear cell renal cell carcinoma.

The cellular response to hypoxia is driven by hypoxia-inducible factors (HIFs), which regulate genes involved in glycolysis, angiogenesis, and cell proliferation, as well as inflammation and tumour progression. HIF activation is well-characterised and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. However, how transcription of individual HIF target genes is regulated at the chromatin level is less clear. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has emerged as a key modulator of HIF target gene transcription. Our study reveals that SET1B interacts with RNA Polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. We also show that in clear cell renal cell carcinoma (ccRCC), SET1B is critical for sustained HIF activity, and SET1B expression correlates with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhances the efficacy of HIF-2 inhibitors, establishing SET1B as a potential therapeutic target in ccRCC.

cancer biology↗

bioRxiv2020

Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1/2-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

cancer biology↗

bioRxiv2019

Hypoxia induces transcriptional and translational downregulation of the type I interferon (IFN) pathway in multiple cancer cell types

Hypoxia is a common phenomenon in solid tumours and is considered a hallmark of cancer. Increasing evidence shows that hypoxia promotes local immune suppression. Type I IFN is involved in supporting cytotoxic T lymphocytes by stimulating the maturation of dendritic cells (DCs) and enhancing their capacity to process and present antigens. However, there is little information about the relationship between hypoxia and the type I interferon (IFN) pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA), followed by IFN/{beta} secretion and transcription activation of IFN-stimulated genes (ISGs). The aims of this study were to determine both the effect and mechanisms of hypoxia on the I IFN pathway in breast cancer.\n\nThere was a downregulation of the type I IFN pathway expression at mRNA and protein level in cancer cell lines under hypoxia in vitro and in vivo in xenografts. This pathway was suppressed at each level of signalling, from the dsRNA sensors (RIG-I, MDA5), the adaptor (MAVS), transcription factors (IRF3, IRF7, STAT1) and several ISGs (RIG-I, IRF7, STAT1, ADAR-p150). There was also lower IFN secretion under hypoxic conditions. HIF1 and HIF2 regulation of gene expression did not explain most of the effects. However, ATAC-Seq data revealed that in hypoxia peaks with STAT1 and IRF3 motifs had decreased accessibility.\n\nThus hypoxia leads to an overall 50% downregulation of the type I IFN pathway due to repressed transcription and lower chromatin accessibility in a HIF1/2-independent manner, which could contribute to immunosuppression in hypoxic tumours.

cancer biology↗