Identification of FOXM1‐induced epigenetic markers for head and neck squamous cell carcinomas

Abstract

BACKGROUND: Epigenetic reprogramming of the methylome has been implicated in all stages of cancer evolution. It is now well accepted that cancer cells exploit epigenetic reprogramming, a mechanism that regulates stem/progenitor cell renewal and differentiation, to promote cancer initiation and progression. The oncogene FOXM1 has been implicated in all major forms of human cancer. METHODS: We have recently shown that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a number of FOXM1-induced epigenetic markers. Differential promoter methylation and gene expression in clinical specimens were measured using commercially available bisulfite conversion kits and absolute quantitative PCR, respectively. RESULTS: Here, we investigated 8 FOXM1-induced differentially methylated genes, SPCS1, FLNA, CHPF, GLT8D1, C6orf136, MGAT1, NDUFA10, and PAFAH1B3, using human head and neck tissue specimens donated by 2 geographically independent patient cohorts from Norway and the United Kingdom. Two genes (GLT8D1 and C6orf136) were found to be differentially expressed in head and neck squamous cell carcinomas (HNSCCs). Using methylationspecific quantitative PCR, we confirmed that the promoters of GLT8D1 and C6orf136 were hypo-and hypermethylated, respectively, in HNSCC tissues. CONCLUSIONS: Given that epigenetic change precedes gene expression, methylation status of candidate genes identified from this study may represent a signature of premalignancy, rendering them potentially useful predictive biomarkers for precancer screening and/or therapeutic targets for cancer prevention. Cancer 2013;119:4249-58.

Initiation of esophageal squamous cell carcinoma (ESCC) in a murine 4-nitroquinoline-1-oxide and alcohol carcinogenesis model

“…More specifically, high expression of FoxM1 induces changes in DNA methylation and epigenetic remodeling programs to maintain stem/progenitor cell renewal and to antagonize pathways inducing differentiation [41, 42]. Modifications in the proliferative nature of stem/progenitor cells have been implicated in the initiation and recurrence of several cancers, including HNSCC and OSCC [43, 44].…”

Glycosylation is a global target for androgen control in prostate cancer cells

“…The large CS proteoglycan Versican is linked to poor prognosis in many different cancer types (Ricciardelli et al 2009b). Differential methylation of CHPF is induced by FOXM1 (Hwang et al 2013) Not reported (Tominaga et al 2014) and confers resistance to docetaxel in breast cancer (Honma et al 2008). Potential biomarker in colorectal cancer .…”

Regulation of prostate cancer progression by the tumor microenvironment

“…Consistent with this concept, using primary normal keratinocytes, Hwang et al found that overexpressing FOXM1 “brainwashed” normal cells to adopt the methylome profile of cancer cells. [95, 96] Moreover, FOXM1 is also important in stem or progenitor cell expansion, which is believed to be involved in cancer initiation. [97] Therefore, combination treatment with small molecules of JQ1 and Siomycin A[98] that target MYC and FOXM1, respectively, might serve as a promising therapeutic strategy to prevent MIC recruitment and reprogramming of surrounding bystander cells halting cancer progression and metastasis (Figure 2).…”