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                <h1 id="record-title" class="wrap-overflowing-text">Promoter methylation leads to Hepatocyte Nuclear Factor 4A loss and pancreatic cancer aggressiveness.</h1>

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          <h3 class="sr-only">Creators</h3>

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    <a class="ui creatibutor-link" data-tooltip="Nottingham Trent University" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Hatziapostolou,+Maria%22">

      <span class="creatibutor-name">Hatziapostolou, Maria

          (Contact person)</span><sup class="font-tiny">1</sup></a>

        <a href="https://orcid.org/0000-0003-2493-7028" aria-label="Hatziapostolou, Maria's ORCID profile" title="Hatziapostolou, Maria's ORCID profile">

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    <a class="ui creatibutor-link" data-tooltip="University of California at Los Angeles" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Marina,+Koutsioumpa%22">

      <span class="creatibutor-name">Marina, Koutsioumpa

          (Other)</span><sup class="font-tiny">2</sup></a>

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    <a class="ui creatibutor-link" data-tooltip="Nottingham Trent" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Polytarchou,+Christos%22">

      <span class="creatibutor-name">Polytarchou, Christos

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    <a class="ui creatibutor-link" data-tooltip="Nottingham Trent University" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22D'Andrea,+Daniel%22">

      <span class="creatibutor-name">D'Andrea, Daniel

          (Contact person)</span><sup class="font-tiny">1</sup></a>

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    <a class="ui creatibutor-link" data-tooltip="Nottingham University Hospitals and University of Nottingham" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Lobo,+Dileep+N%22">

      <span class="creatibutor-name">Lobo, Dileep N

          (Other)</span><sup class="font-tiny">4</sup></a>

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    <a class="ui creatibutor-link" data-tooltip="University of California" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Dawson,+David+W%22">

      <span class="creatibutor-name">Dawson, David W

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    <a class="ui creatibutor-link" data-tooltip="University of California at Los Angeles" href="https://zenodo.org/search?q=metadata.creators.person_or_org.name:%22Iliopoulos,+Dimitrios%22">

      <span class="creatibutor-name">Iliopoulos, Dimitrios

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      Nottingham Trent University

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      University of California at Los Angeles

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      Nottingham Trent

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      Nottingham University Hospitals and University of Nottingham

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      University of California

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      <p><i>Efforts to decode pancreatic ductal adenocarcinoma (PDAC) heterogeneity and the consequent therapeutic selection remains a challenge. We aimed to characterize epigenetically regulated pathways involved in PDAC progression.</i></p><p><i>Global DNA methylation analysis in pancreatic cancer patient tissues and cell lines was performed to identify differentially methylated genes. Targeted bisulfite sequencing and in vitro methylation reporter assays were employed to investigate the direct link between sitespecific methylation and transcriptional regulation. A series of in vitro loss- and gain-of function studies, and in vivo xenograft and the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) mouse models were used to assess pancreatic cancer cell properties. Gene and protein expression analyses were performed in three different cohorts of pancreatic cancer patients and correlated to clinicopathological parameters.</i></p><p><i>We identify Hepatocyte Nuclear Factor 4A (HNF4A) as a novel target of hypermethylation in pancreatic cancer and demonstrate that site-specific proximal promoter methylation drives HNF4A transcriptional repression. Expression analyses in patients, indicate the methylation-associated suppression of HNF4A expression in pancreatic cancer tissues. In vitro and in vivo studies reveal that HNF4A is a novel tumor suppressor in pancreatic cancer, regulating cancer growth and aggressiveness. As evidenced in both the KPC mouse model and human pancreatic cancer tissues, HNF4A expression declines significantly in the early stages of the disease. Most importantly, HNF4 loss correlates with poor overall patient survival.</i></p>

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