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Down‐regulation of HLA Class I and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells
Author(s) -
Sers Christine,
Kuner Ruprecht,
Falk Christine S.,
Lund Per,
Sueltmann Holger,
Braun Monika,
Buness Andreas,
Ruschhaupt Markus,
Conrad Janine,
MangFatehi Shila,
Stelniec Iwona,
Krapfenbauer Ulf,
Poustka Annemarie,
Schäfer Reinhold
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24557
Subject(s) - dna methyltransferase , methyltransferase , biology , dna methylation , nkg2d , epigenetics , cancer research , mapk/erk pathway , methylation , human leukocyte antigen , immune system , microbiology and biotechnology , antigen , gene , gene expression , immunology , cytotoxic t cell , genetics , signal transduction , in vitro
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. © 2009 UICC