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@ARTICLE{Faltus:181843,
      author       = {C. Faltus$^*$ and A. Lahnsteiner and M. Barrdahl$^*$ and Y.
                      Assenov$^*$ and A. Hüsing$^*$ and O. Bogatyrova$^*$ and M.
                      Laplana$^*$ and T. S. Johnson$^*$ and T. Muley and M.
                      Meister and A. Warth and M. Thomas and C. Plass$^*$ and R.
                      Kaaks$^*$ and A. Risch$^*$},
      title        = {{I}dentification of {NHLRC}1 as a {N}ovel {AKT} {A}ctivator
                      from a {L}ung {C}ancer {E}pigenome-{W}ide {A}ssociation
                      {S}tudy ({EWAS}).},
      journal      = {International journal of molecular sciences},
      volume       = {23},
      number       = {18},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2022-02258},
      pages        = {10699},
      year         = {2022},
      note         = {#EA:B370#LA:B370#},
      abstract     = {Changes in DNA methylation identified by epigenome-wide
                      association studies (EWAS) have been recently linked to
                      increased lung cancer risk. However, the cellular effects of
                      these differentially methylated positions (DMPs) are often
                      unclear. Therefore, we investigated top differentially
                      methylated positions identified from an EWAS study. This
                      included a putative regulatory region of NHLRC1.
                      Hypomethylation of this gene was recently linked with
                      decreased survival rates in lung cancer patients.
                      HumanMethylation450 BeadChip array (450K) analysis was
                      performed on 66 lung cancer case-control pairs from the
                      European Prospective Investigation into Cancer and Nutrition
                      Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs
                      identified in these pre-diagnostic blood samples were then
                      investigated for differential DNA methylation in lung tumor
                      versus adjacent normal lung tissue from The Cancer Genome
                      Atlas (TCGA) and replicated in two independent lung tumor
                      versus adjacent normal tissue replication sets with
                      MassARRAY. The EPIC HD top hypermethylated DMP cg06646708
                      was found to be a hypomethylated region in multiple data
                      sets of lung tumor versus adjacent normal tissue.
                      Hypomethylation within this region caused increased mRNA
                      transcription of the closest gene NHLRC1 in lung tumors. In
                      functional assays, we demonstrate attenuated proliferation,
                      viability, migration, and invasion upon NHLRC1 knock-down in
                      lung cancer cells. Furthermore, diminished AKT
                      phosphorylation at serine 473 causing expression of
                      pro-apoptotic AKT-repressed genes was detected in these
                      knock-down experiments. In conclusion, this study
                      demonstrates the powerful potential for discovery of novel
                      functional mechanisms in oncogenesis based on EWAS DNA
                      methylation data. NHLRC1 holds promise as a new prognostic
                      biomarker for lung cancer survival and prognosis, as well as
                      a target for novel treatment strategies in lung cancer
                      patients.},
      keywords     = {DNA methylation (Other) / EWAS (Other) / NHLRC1 (Other) /
                      PI3K pathway activation (Other) / lung cancer (Other)},
      cin          = {B370 / C020},
      ddc          = {540},
      cid          = {I:(DE-He78)B370-20160331 / I:(DE-He78)C020-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36142605},
      doi          = {10.3390/ijms231810699},
      url          = {https://inrepo02.dkfz.de/record/181843},
}