Down-Regulation of Serum/Glucocorticoid Regulated Kinase 1 in Colorectal Tumours Is Largely Independent of Promoter Hypermethylation

Abstract

BackgroundWe have previously shown that serum/glucocorticoid regulated kinase 1 (SGK1) is down-regulated in colorectal cancers (CRC) with respect to normal tissue. As hyper-methylation of promoter regions is a well-known mechanism of gene silencing in cancer, we tested whether the SGK1 promoter region was methylated in colonic tumour samples.Methodology/Principal FindingsWe investigated the methylation profile of the two CpG islands present in the promoter region of SGK1 in a panel of 5 colorectal cancer cell lines by sequencing clones of bisulphite-treated DNA samples. We further confirmed our findings in a panel of 10 normal and 10 tumour colonic tissue samples of human origin. We observed CpG methylation only in the smaller and more distal CpG island in the promoter region of SGK1 in both normal and tumour samples of colonic origin. We further identified a single nucleotide polymorphism (SNP, rs1743963) which affects methylation of the corresponding CpG.Conclusions/SignificanceOur results show that even though partial methylation of the promoter region of SGK1 is present, this does not account for the different expression levels seen between normal and tumour tissue.

Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis

“…In terms of regulation of SGK1 expression, in CRC, mutations in SGK1 may be observed in up to 2% of cases, although the mutations are usually missense and not isolated to the kinase domain [38]. Our previous work has identified that down-regulation in CRCs appears to be independent of promoter hypermethylation [39] and these observations suggest that control is likely to be transcriptionally regulated.…”

Low SGK1 Expression in Human Adrenocortical Tumors Is Associated with ACTH-Independent Glucocorticoid Secretion and Poor Prognosis

“…Accordingly, high SGK1 expression has been implicated in cell survival in different neoplasias (7, 8, 12–14). However, the role of SGK1 in cancer cells may be rather complex and largely dependent on the cellular context, because in some cancers SGK1 expression is down-regulated (8, 15, 16). The negative predictive role of low SGK1 expression in ACC in our study was robust and remained evident also after adjustment for multiple prognostic factors including GC secretion and tumor stage.…”

“…prostate, hepatocellular, and colorectal cancer) (8, 15, 16). The impact of SGK1 expression on clinical outcome has been evaluated only in a small number of studies, again with contradictory results in different cancers (14, 17).…”

SGK1 in Human Cancer: Emerging Roles and Mechanisms

“…In solid tumors, SGK1 is often upregulated in most of the cancer, such as adrenocortical adenomas ( 26 ), breast cancer ( 14 ), endometrial cancer ( 30 ), gastric cancer (GC) ( 15 ), lung cancer ( 16 , 17 , 31 ), medulloblastoma ( 32 ), oral squamous cell carcinoma (OSCC) ( 33 ), ovarian cancer ( 34 ), prostate carcinoma ( 20 , 35 ), renal clear cell carcinoma ( 32 ), and rhabdomyosarcoma ( 36 ). Although the exact reason why SGK1 expression in cancer in the intestinal system is downregulated remains unclear ( 24 , 25 ), it has been postulated to most likely be due to transcriptional repressors acting on the SGK1 promoter ( 37 ). What these repressors are and how they are controlled remains unclear ( 37 ).…”