FOXM1 Induces a Global Methylation Signature That Mimics the Cancer Epigenome in Head and Neck Squamous Cell Carcinoma

Abstract

The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates HELLS, a SNF2/helicase involved in DNA methylation, implicating FOXM1 in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of FOXM1 suppressed the tumour suppressor gene p16INK4A (CDKN2A) through promoter hypermethylation. Knockdown of HELLS using siRNA re-activated the mRNA expression of p16INK4A and concomitant downregulation of two DNA methyltransferases DNMT1 and DNMT3B. The dose-dependent upregulation of endogenous FOXM1 (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of HELLS, BMI1, DNMT1 and DNMT3B and negatively with p16INK4A and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of FOXM1 significantly induced p16INK4A promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant FOXM1 expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with in vivo mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique FOXM1-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions.

FOXM1 is a therapeutic target for high-risk multiple myeloma

“…Further encouraged by new evidence indicating that FOXM1 (1) drives tumor development and progression 15–19 by virtue of a complex mechanism that includes enhanced cell proliferation, migration and invasion 6 , regulation of the DNA damage response 20 and changes in the cancer epigenome 21 , (2) promotes cancer-cell resistance to ionizing radiation 22 and cytotoxic drugs 23 , (3) governs, in part, the survival and tissue-regenerating capacity of both normal hematopoietic stem cells 24 and malignant stem cell-like cells 25 , (4) links acquired resistance to cancer therapy with cancer stemness 26 and (5) owing to the development of specific small-molecule inhibitors 27 , may soon be targeted more effectively than possible in the past 28 , we here decided to evaluate whether FOXM1 might play an important but heretofore overlooked role in plasma cell myeloma.…”

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].…”

HELLS (Helicase, Lymphoid-Specific)

“…Additionally, HELLS is known to be involved in control of p16 tumor suppressor gene expression through repression with reduction in HELLS leading to increased p16 expression. FOXM1 also suppresses p16, likely through HELLS induction (Teh et al, 2012). This also leads to a DNA methylation profile in primary oral keratinocytes that is similar to human head and neck cancer (Teh et al, 2012).…”

“…FOXM1 also suppresses p16, likely through HELLS induction (Teh et al, 2012). This also leads to a DNA methylation profile in primary oral keratinocytes that is similar to human head and neck cancer (Teh et al, 2012).…”