title: Down-regulation of HLA Class I and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells.
abstract: Most malignant features of cancer cells are triggered by activated oncogenes and the loss of tumor suppressors due to mutation or epigenetic inactivation. It is still unclear, to what extend the escape of emerging cancer cells from recognition and elimination by the immune system is determined by similar mechanisms. We compared the transcriptomes of HCT116 colorectal cancer cells deficient in DNA methyltransferases (DNMTs) and of cells, in which the RAS pathway as the major growth-promoting signaling system is blocked by inhibition of MAPK. We identified the MHC Class I genes HLA-A1/A2 and the ULBP2 gene encoding 1 of the 8 known ligands of the activating NK receptor NKG2D among a cluster of immune genes up-regulated under the conditions of both DNMT-deficiency and MEK-inhibition. Bisulphite sequencing analyses of HCT116 with DNMT deficiency or after MEK-inhibition showed that de-methylation of the ULPB2 promoter correlated with its enhanced surface expression. The HLA-A promoters were not methylated indicating that components of the HLA assembly machinery were also suppressed in DNMT-deficient and MEK-inhibited cells. Increased HLA-A2 surface expression was correlated with enhanced recognition and lysis by A2-specific CTL. On the contrary, elevated ULBP2 expression was not reflected by enhanced recognition and lysis by NK cells. Cosuppression of HLA Class I and NKG2D ligands and genes encoding peptide transporters or proteasomal genes mediates a strong functional link between RAS activation, DNMT activity and disruption of the antigen presenting system controlling immune recognition in colorectal cancer cells.
authors: Institute of Pathology, Charité, Universitätsmedizin Berlin, Berlin, Germany. christine.sers@charite.de
authors: Christine
authors: C
authors: Sers
authors: Ruprecht
authors: R
authors: Kuner
authors: Christine S
authors: CS
authors: Falk
authors: Per
authors: P
authors: Lund
authors: Holger
authors: H
authors: Sueltmann
authors: Monika
authors: M
authors: Braun
authors: Andreas
authors: A
authors: Buness
authors: Markus
authors: M
authors: Ruschhaupt
authors: Janine
authors: J
authors: Conrad
authors: Shila
authors: S
authors: Mang-Fatehi
authors: Iwona
authors: I
authors: Stelniec
authors: Ulf
authors: U
authors: Krapfenbauer
authors: Annemarie
authors: A
authors: Poustka
authors: Reinhold
authors: R
authors: Schäfer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D000077157:Sorafenib; D018631:ras Proteins / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D002070:Butadienes; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen; D036341:Intercellular Signaling Peptides and Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D009536:Niacinamide; D009570:Nitriles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines; D000077157:Sorafenib; D018631:ras Proteins; D000097584:DNA Methyltransferase 3B; C117307:KRAS protein, human; C113580:U 0126; C423230:ULBP2 protein, human