Biology subjects

Koivunen, P.

Publications and source records attributed to Koivunen, P..

5 recordsLinked to original sources

bioRxiv2022

A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreas cancer

Here, we show that hypoxia drives especially long-lasting epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) primarily through a positive-feedback histone methylation-MAPK signaling axis. We find that transformed cells preferentially undergo EMT in hypoxic tumor regions in multiple model systems and that hypoxia drives a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, can last for weeks. We further demonstrate that hypoxia reduces histone demethylase KDM2A activity, suppresses PP2 family phosphatase expression, and activates MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors play only a supporting role. This mechanism can be antagonized in vivo by combinations of MAPK inhibitors that may be effective in multi-drug therapies designed to target EMT.

cancer biology↗

bioRxiv2020

Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains

Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a poorly characterized endoplasmic reticulum (ER)-localized transmembrane prolyl 4-hydroxylase (P4H-TM) is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome. Here, the 3D structure of the soluble human P4H-TM was solved using X-ray crystallography. The structure revealed an EF-domain with two Ca2+-binding motifs inserted to the catalytic domain. A substrate-binding cavity was formed between the EF-domain and the catalytic domain. The active site contained bound Fe2+ and N-oxalylglycine. Comparison to homologous structures complexed with peptide substrates showed that the substrate interacting residues and the lid structure that folds over the substrate are conserved in P4H-TM. Differences to homologs were found in the extensive loop structures that surround the substrate-binding cavity and generate a negative surface charge. Ca2+-binding affinity of P4H-TM was determined to be within the range of physiological Ca2+ concentration in the ER. The proximity of the EF-domain to the active site suggests that Ca2+-binding is relevant to the catalytic activity. P4H-TM was found both as a monomer and a dimer in solution, but the monomer-dimer equilibrium was not regulated by Ca2+. The solved 3D structure suggests that the HIDEA variants cause loss of P4H-TM function. In conclusion, P4H-TM shares key structural elements with the known P4Hs while possessing a unique property among the 2-oxoglutarate-dependent dioxygenases having an EF-domain and a catalytic activity potentially regulated by Ca2+.

biochemistry↗

bioRxiv2019

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

Mammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF- and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.\n\nOne Sentence SummaryKDM6A demethylase activity is diminished under hypoxic conditions and causes changes in gene expression programs that govern cell fate.

biochemistry↗

bioRxiv2018

Lower hemoglobin levels associate with lower body mass index and healthier metabolic profile

Hemoglobin (Hb) is the main carrier of oxygen. In general, high-end Hb levels within the normal range are considered beneficial for health1. However, activation of the hypoxia response has been shown to protect mice against metabolic dysfunction2-4. We used Hb levels as an indicator for oxygenation status and studied its association with >170 anthropometric and metabolic parameters in two Finnish birth cohorts both in cross-sectional and longitudinal design (max n = 7,175). Here we show a positive linear association between Hb levels and body mass index (BMI). Subjects with the lower Hb levels had better glucose tolerance, lower cholesterol and blood pressure levels, less adverse metabolite profiles and lower inflammatory load. Notably, these associations were not only mediated by the lower BMI, and the effect size of many of them increased with age. Polygenic risk score (PRS) analyses indicated shared genetic determinants between Hb levels and BMI, insulin, triglyceride and HDL cholesterol levels. Mendelian randomization (MR) analyses could not demonstrate causal relationships between Hb and metabolic parameters. However, manipulation of Hb levels by venesection in mice showed evidence for causal associations with body weight and metabolic parameters. Our findings suggest that lower-end normal Hb levels may be favorable for systemic metabolism involving mild chronic activation of the hypoxia response. Therefore modulation of Hb levels could be a novel strategy towards maintenance of metabolic health.

epidemiology↗

bioRxiv2018

The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2

The EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.

biochemistry↗