Epigenetic Silencing of HOPX Promotes Cancer Progression in Colorectal Cancer

Abstract

Homeodomain-only protein X (HOPX)-β promoter methylation was recently shown to be frequent in human cancers and was suggested as tumor suppressor gene in esophageal and gastric cancer. The aim of this study was to investigate the mechanistic roles of HOPX-β promoter methylation and its clinical relevance in colorectal cancer (CRC). HOPX-β promoter methylation was assessed in human CRC cell lines and 294 CRC tissues. HOPX mRNA and protein levels were measured in relation to HOPX-β promoter methylation. The effects of forced HOPX expression on tumorigenesis were studied using in vitro and in vivo assays. The association between HOPX-β promoter methylation and clinical relevance of CRC patients was determined. HOPX-β promoter methylation is cancer-specific and frequently found in CRC cell lines and tissues, resulting in the down-regulation of HOPX mRNA and protein levels. In CRC cell lines, forced expression of HOPX suppressed proliferation, invasion, and anchorage-independent growth. DNA microarray analyses suggested critical downstream genes that are associated with cancer cell proliferation, invasion or angiogenesis. In a mouse xenograft model, HOPX inhibited tumorigenesis and angiogenesis. Finally, HOPX-β promoter methylation was associated with worse prognosis of stage III CRC patients (hazard ratio= 1.40, P = .035) and also with poor differentiation (P = .014). In conclusion, HOPX-β promoter methylation is a frequent and cancer-specific event in CRC progression. This epigenetic alteration may have clinical ramifications in the diagnosis and treatment of CRC patients.

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

“…Our data suggests that aberrant hypermethylation of the WIF-1 promoter is an important epigenetic event leading to WIF-1 downregulation in neuroblastoma. Aberrant methylation of promoter regions that silence gene transcription has been recognized as a mechanism for inactivating tumor suppressor genes in some cancers [31,32]. WIF-1 silencing due to promoter methylation has also been recognized to facilitate tumorigenesis in nasopharyngeal and lung cancer, hepatocellular carcinoma, and colorectal cancer [33][34][35][36][37].…”

Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer

“…In the development of CRC, growing numbers of tumor suppressor genes have been reported to be inactivated by genetic and epigenetic alterations [2,3]. Promoter hypermethylation, one of the well-studied epigenetic modifications, has been recognized as an important mechanism for gene silencing during the early stage of CRC development, which highlights the importance of promoter hypermethylation in the tumorigenesis of CRC and provide important biomarkers for CRC [4,5].…”

Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy

“…Considering that epigenetic alteration in HOPX gene promoter was found related to some cancers (42,43), and that methylation level in exonic CpG sites of cardiac MYBPC3 gene, a common causal gene for HCM, may result in increased genetic mutability (44), epigenetic evaluation of HOPX gene promoter is wothy of investigation in HCM patients.…”