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000181843 1001_ $$0P:(DE-He78)9ffda9a3f56756b7ca362c1f07738242$$aFaltus, Christian$$b0$$eFirst author
000181843 245__ $$aIdentification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS).
000181843 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2022
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000181843 520__ $$aChanges in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.
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000181843 650_7 $$2Other$$aDNA methylation
000181843 650_7 $$2Other$$aEWAS
000181843 650_7 $$2Other$$aNHLRC1
000181843 650_7 $$2Other$$aPI3K pathway activation
000181843 650_7 $$2Other$$alung cancer
000181843 7001_ $$00000-0001-7402-3369$$aLahnsteiner, Angelika$$b1
000181843 7001_ $$0P:(DE-He78)9c1a5b028ca0ab2ef3468a9266f81f63$$aBarrdahl, Myrto$$b2
000181843 7001_ $$0P:(DE-He78)45a6854ecf41ba2e65ca3ba0d560f14c$$aAssenov, Yassen$$b3
000181843 7001_ $$0P:(DE-He78)6519c85d61a3def7974665471b8a4f74$$aHüsing, Anika$$b4
000181843 7001_ $$0P:(DE-He78)3493620cedb8f0b17c9e1b424c0e21db$$aBogatyrova, Olga$$b5
000181843 7001_ $$0P:(DE-He78)e7d83ba57c27ef97b4cd5b96693bea0f$$aLaplana, Marina$$b6
000181843 7001_ $$0P:(DE-He78)79ab945544e5bc017a2317b6146ed3aa$$aJohnson, Theron Scot$$b7$$udkfz
000181843 7001_ $$00000-0002-8141-0604$$aMuley, Thomas$$b8
000181843 7001_ $$aMeister, Michael$$b9
000181843 7001_ $$aWarth, Arne$$b10
000181843 7001_ $$aThomas, Michael$$b11
000181843 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b12$$udkfz
000181843 7001_ $$0P:(DE-He78)4b2dc91c9d1ac33a1c0e0777d0c1697a$$aKaaks, Rudolf$$b13$$udkfz
000181843 7001_ $$0P:(DE-He78)4981f4ef151aea881f38b33df8e35a21$$aRisch, Angela$$b14$$eLast author
000181843 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms231810699$$gVol. 23, no. 18, p. 10699 -$$n18$$p10699$$tInternational journal of molecular sciences$$v23$$x1422-0067$$y2022
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