Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes

Abstract

BackgroundThe human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus. This indicates that upregulation of FOXM1 may be an early molecular signal required for aberrant cell cycle and cancer initiation.ResultsThe present study investigated the putative early mechanism of UVB and FOXM1 in skin cancer initiation. We have demonstrated that UVB dose-dependently increased FOXM1 protein levels through protein stabilisation and accumulation rather than de novo mRNA expression in human epidermal keratinocytes. FOXM1 upregulation in primary human keratinocytes triggered pro-apoptotic/DNA-damage checkpoint response genes such as p21, p38 MAPK, p53 and PARP, however, without causing significant cell cycle arrest or cell death. Using a high-resolution Affymetrix genome-wide single nucleotide polymorphism (SNP) mapping technique, we provided the evidence that FOXM1 upregulation in epidermal keratinocytes is sufficient to induce genomic instability, in the form of loss of heterozygosity (LOH) and copy number variations (CNV). FOXM1-induced genomic instability was significantly enhanced and accumulated with increasing cell passage and this instability was increased even further upon exposure to UVB resulting in whole chromosomal gain (7p21.3-7q36.3) and segmental LOH (6q25.1-6q25.3).ConclusionWe hypothesise that prolonged and repeated UVB exposure selects for skin cells bearing stable FOXM1 protein causes aberrant cell cycle checkpoint thereby allowing ectopic cell cycle entry and subsequent genomic instability. The aberrant upregulation of FOXM1 serves as a 'first hit' where cells acquire genomic instability which in turn predisposes cells to a 'second hit' whereby DNA-damage checkpoint response (eg. p53 or p16) is abolished to allow damaged cells to proliferate and accumulate genetic aberrations/mutations required for cancer initiation.

Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential

“…Aberrant activation of FoxM1 has been correlated with chromosomal instability. 21 Consistent with this role, we found a high number of triple spindles in synchronised K38 keratinocyte cells stably transduced with Snail compared with control cells (Figure 3e). …”

“…It has been shown that FoxM1 upregulation induces genomic instability in epidermal keratinocytes. 21 We also show that cells expressing Snail in a malignant context have an increased resistance to genotoxic and other forms of stress. This survival advantage has been previously demonstrated in the recurrence of breast cancer accompanied by an EMT phenotype and strong expression of Snail.…”

Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling

“…FOXM1 is thought to promote oncogenesis through its multiple roles in cell cycle and chromosomal/genomic maintenance (29). Aberrant up-regulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity and CNAs (30). A recent report showed that aberrant up-regulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system, a condition similar to human hyperplasia (31).…”

Quantitative study of epigenetic signature in head >and necksquamous cell carcinoma

“…There are a number of carcinogenic and environmental factors that activate FOXM1, resulting in uncontrolled cell proliferation and malignant transformation: for example, nicotine in tobacco (4), oxidative stress (27,28), UV light (29), and ionizing irradiation (19). These factors are reported to aberrantly increase FOXM1 expression levels, which induces genomic instability and epigenetic modification by activating downstream targets HELLS and CEP55 protein.…”

“…Oral SCC cell line SCC15 (32) is a well-established cell line cultured as described earlier (4,5,29).…”