Differential but Complementary HIF1α and HIF2α Transcriptional Regulation

Downes, Nicholas; Laham-Karam, Nihay; Kaikkonen, Minna U.; Ylä‐Herttuala, Seppo

doi:10.1016/j.ymthe.2018.05.004

Cited by 122 publications

(132 citation statements)

References 44 publications

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“…In the canonical hypoxia‐mediated transcription pathway, HIF‐1α/2α‐HIF‐1β heterodimer binds to the HRE characterized by a conserved RCGTG DNA motif . HIF‐1α/2α have been implicated in transcriptionally regulating themselves in a positive feedback manner, and canonical target genes associated with the promoter histone modification, along with the cofactor involvement, may represent additional layers of regulation . Indeed, our data revealed that ectopically overexpressed SphK2 led enhanced promoter occupancy of HIF‐1α protein on the HIF‐2α promoter, and conversely, knockdown of SphK2 led reduced hypoxia‐mediated HIF‐1α binding of the HIF‐2α promoter in breast cancer cells (Figure ).…”

Section: Discussionmentioning

confidence: 74%

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Hait

Maiti

et al. 2020

FASEB j.

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Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine‐1‐phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia‐responsive master transcription factors hypoxia‐inducible factor (HIF)‐1α/2α, and their functions in breast cancer, with a focus on triple‐negative breast cancer (TNBC). We have shown SphK2 is associated with HIF‐1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF‐1α. SphK2, and HIF‐1α expression levels are elevated in metastatic estrogen receptor‐positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K‐145, that nuclear S1P, histone acetylation, HIF‐1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF‐1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.

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Section: Discussionmentioning

confidence: 74%

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Hait

Maiti

et al. 2020

FASEB j.

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“…Extensive transcriptional analysis in endothelial cells revealed that HIF-1␣ and HIF-2␣ regulated 701 and 1,454 genes, respectively. HIF-1␣ transcription involved primarily metabolic reprogramming, whereas HIF-2␣ appeared to regulate angiogenic signaling and extracellular matrix remodeling (65). In another study, vGPCR was found to be a novel target of HIF-1␣ and one of the main viral angiogenic factors regulating the metabolic reprogramming of KSHV (21).…”

Section: Discussionmentioning

confidence: 97%

The Kaposi’s Sarcoma-Associated Herpesvirus ORF34 Protein Interacts and Stabilizes HIF-2α via Binding to the HIF-2α bHLH and PAS Domains

Haque

Kousoulas

2019

J Virol

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Hypoxia and hypoxia inducible factors (HIFs) play important roles in the Kaposi’s sarcoma-associated herpesvirus (KSHV) life cycle. KSHV is the causative agent of Kaposi’s sarcoma (KS) and other AIDS-related malignancies. Kaposi’s sarcoma is a highly vascular tumor, which preferentially develops in the lower extremities of the body where blood vessels are often poorly oxygenated. The main cellular responses to hypoxia are mediated mainly by two isoforms of HIF, HIF-1α and HIF-2α. HIF-1α and HIF-2α have common as well as distinct functions, although they are similar in structure and function. Previously, we showed that the KSHV ORF34 protein binds HIF-1α and facilitates its degradation through the ubiquitin-proteasome pathway causing negative regulation of HIF-1α-dependent genes (Haque and Kousoulas, J Virol 87:2164-2173, 2013, https://www.doi.org/10.1128/JVI.02460-12). Herein, we show that theORF34gene is involved in the regulation of KSHV lytic gene expression, since deletion ofORF34resulted in reduced immediate early and early lytic gene expression and blocked late gene expression. Coimmunoprecipitation experiments revealed that the ORF34 protein physically interacted with HIF-2α in transfected as well as in KSHV-infected cells. Utilization of ORF34 truncations revealed that three distinct domains bind HIF-2α and that both bHLH and PAS domains of HIF-2α interacted with ORF34. Unlike HIF-1α, dose-dependent coexpression of ORF34 stabilized the HIF-2α protein, ensuring HIF-2α-dependent transcriptional activity. The ORF34 protein enhanced HIF-2α ubiquitination at the bHLH and PAS domains. The results show that the KSHV ORF34 protein is involved in the KSHV life cycle by regulating the expression of HIF-1α and HIF-2α proteins.IMPORTANCEHypoxia inducible factor 1α (HIF-1α) and HIF-2α are transcription factors which play important roles in the Kaposi’s sarcoma-associated herpesvirus (KSHV) latent and lytic gene replication. Herein, we show that theORF34gene is involved in the regulation of KSHV lytic gene expression, since deletion ofORF34resulted in reduced immediate early and early lytic gene expression and blocked late gene expression. In addition, we demonstrate that the KSHV ORF34 protein binds and stabilizes HIF-2α, in contrast to its role in binding HIF-1α and causing its degradation via the proteasome pathway. Thus, the KSHV ORF34 protein plays a regulatory role in the KSHV life cycle by regulating HIF-1α and HIF-2α expression.

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“…Myeloid cells have an active role in that process, acting as cellular chaperones to promote endothelial tip cell fusion during vessel formation and producing proangiogenic factors [20,21]. HIF2α modulates HIF1α-driven proangiogenic responses by expressing sFlt1, stabilizing proliferating vessels, and promoting healthy revascularization [22]; HIF1 and HIF2 bind to different HREs in gene promoters, both being required for maximal transcriptional activity [23].…”

Section: Discussionmentioning

confidence: 99%

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia

et al. 2019

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The retinal vasculature is tightly organized in a structure that provides for the high metabolic demand of neurons while minimizing interference with incident light. The adverse impact of retinal vascular insufficiency is mitigated by adaptive vascular regeneration but exacerbated by pathological neovascularization. Aberrant growth of neovessels in the retina is responsible for impairment of sight in common blinding disorders including retinopathy of prematurity, proliferative diabetic retinopathy, and age-related macular degeneration. Myeloid cells are key players in this process, with diverse roles that can either promote or protect against ocular neovascularization. We have previously demonstrated that myeloid-derived VEGF, HIF1, and HIF2 are not essential for pathological retinal neovascularization. Here, however, we show by cell-specific depletion of Vhl in a mouse model of retinal ischemia (oxygen-induced retinopathy, OIR) that myeloid-derived HIFs promote VEGF and bFGF expression and enhance vascular regeneration in association with improved density and organization of the astrocytic network.

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Differential but Complementary HIF1α and HIF2α Transcriptional Regulation

Cited by 122 publications

References 44 publications

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

The Kaposi’s Sarcoma-Associated Herpesvirus ORF34 Protein Interacts and Stabilizes HIF-2α via Binding to the HIF-2α bHLH and PAS Domains

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia

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