| Shrnutí: | <p>The ability to sense and respond to hypoxia is essential for the survival of living organisms and is frequently co-opted by tumor cells to adapt to hypoxic microenvironment. As the pivotal transcription factor for hypoxic responses, the hypoxia inducible factors (HIFs) transactivate a wide repertoire of genes that can mediate divergent functional outcomes. The regulation of HIF target gene selectivity is complex, involving the canonical regulation by oxygen sensors prolyl hydroxylases and factor inhibiting HIF (FIH) and the regulated recruitment of transcriptional cofactors, such as p300. However, how HIF target gene selectivity is regulated in cancers has yet to be fully understood.</p>
<p>Apoptosis stimulating protein of p53 2 (ASPP2) belongs to the ASPP protein family whose members are established regulators of p53-family proteins. Recently, it was found that ASPP2 is one of the alternative substrates of FIH and may be a potential competitor of HIFalpha for FIH activity. However, whether ASPP2 plays a role in the regulation of HIF activity in cancer remains unclear. </p>
<p>In this work we showed that ASPP2 regulates the expression of a subset of HIF target genes irrespective of FIH status. Using HIF target gene EGLN3 for further investigation, we further found that ASPP2 does not affect either the protein expression, subcellular localization, or the level of DNA-binding of HIFs to the HRE-containing EGLN3 loci. </p>
<p>To explore whether ASPP2 modulates the expression of EGLN3 and potentially other ASPP2-sensitive HIF targets through regulating another signaling pathway that crosstalks with HIFs at the transcriptional level, we constructed a bioinformatics pipeline that combines gene coexpression analysis and gene set enrichment analysis to successfully identify both known and hitherto unknown ASPP2-coexpressed pathways at a pan-cancer level. </p>
<p>Among these ASPP2-coexpressed pathways, we focused on the hippo pathway in which transcriptional coactivator YAP has previously been reported to act as a transcriptional cofactor of HIF1alpha. We found that the loss of ASPP2 reduces the nuclear localization of YAP under hypoxia. It also attenuates the nuclear interaction between YAP and HIF1alpha, as well as the level of DNA-binding of YAP at HRE-containing loci of EGLN3. </p>
<p>Overall, this study demonstrates for the first time that ASPP2 modulates a subset of HIF target gene expression, potentially by regulating the interaction between YAP and HIF1alpha. Our work also identifies novel pan-cancer ASPP2-associated pathways that would assist in unlocking hypothesis to expand the functions of ASPP2 in human cancers and beyond. </p>
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