# HIF-2α Interaction with Ataxin-10 Enhances HIF-2α Binding to Its Target Gene Promoters

## TL;DR

This study shows that HIF-2α interacts with Ataxin-10, boosting its ability to activate genes under low oxygen conditions, which could lead to new cancer treatments.

## Contribution

The novel contribution is the discovery that Ataxin-10 enhances HIF-2α transcriptional activity by increasing its binding to target gene promoters.

## Key findings

- Ataxin-10 binds to the HIF-2α carboxyterminal activation domain.
- HIF-2α interaction with Ataxin-10 increases transcriptional activity under hypoxia.
- This interaction enhances HIF-2α binding to promoters of genes like SERPINE1, CITED-2, and SOD-2.

## Abstract

The master transcription factors that control cell adaptation under hypoxia are known as hypoxia-inducible factors or HIFs. HIF-2α is the second isoform, which has been studied less extensively, and its expression is limited to particular cell types and is associated with increased malignancy in tumors. Herein, we investigate the interaction of HIF-2α with Ataxin-10, an intracellular protein involved in cell survival and differentiation, as well as the mechanism and the effects of this interaction in cervical cancer (HeLa) and glioma (U-87MG) cells. The interaction was investigated by LC-MS/MS proteomic analysis, immunoprecipitation, and immunoblotting. HIF-2 transcriptional activity was measured by luciferase assays and quantitative RT-PCR of target genes specific to HIF-2. The mechanism of interaction was investigated using immunofluorescence microscopy analysis, subcellular fractionation, siRNA-mediated silencing, quantitative RT-PCR, in vitro binding assays, and chromatin immunoprecipitation (ChIP). Ataxin interacts specifically with HIF2α and binds to the HIF-2α carboxyterminal activation domain. The interaction of HIF-2α with Ataxin-10 increases HIF-2-transcriptional activity under hypoxia through the enhancement of HIF-2α binding to chromatin in Hypoxia Response Elements of HIF-2 specific target genes SERPINE1, CITED-2, and SOD-2. These new data highlight a novel HIF-2 fine-tuning mechanism and may offer new, effective therapeutic approaches for treating cancerous tumors.