Abstract
FOXM1 (forkhead box protein M1) is a transcription factor that participates in all stages of tumor development, mainly through the control of cell cycle and proliferation, regulating the expression of genes involved in G1/S and G2/M transition and M phase progression. The ubiquitin conjugating enzyme E2 (UBE2C) is a member of the anaphase promoting complex/cyclosome, promoting the degradation of several target proteins along cell cycle progression, during metaphase/anaphase transition. FOXM1 and UBE2C have been found overexpressed in a wide range of different solid tumors. Therefore, the aim of this study was to investigate whether UBE2C is a transcriptional target of FOXM1, using esophageal squamous cell carcinoma (ESCC) as a model, in addition to several cancer-deposited data. Our results show that FOXM1 and UBE2C expression present a positive correlation in normal tissues and in 25 distinct tumor types, including ESCC, where these genes are overexpressed. Moreover, FOXM1 binds to UBE2C promoter region in ESCC cell line and transcriptionally activates it, leading to UBE2C upregulation. In conclusion, this study provides evidences that FOXM1 transcriptionally regulates UBE2C expression in ESCC and their deregulation may be a general phenomenon in human neoplasias.
Highlights
Forkhead box protein M1 (FOXM1) is one of the most studied members of the FOX transcriptional regulators family [1], characterized by an evolutionary conserved ‘forkhead’ or ‘winged-helix’DNA-binding domain (DBD) [2]
FOXM1 and UBE2C gene expression profiles were analyzed in samples from 27 different healthy tissues, using sequence read archive (SRA) data, bioproject PRJEB4337, and a very similar expression pattern was observed for these two genes (Figure 1A)
We re-analyzed FOXM1 and UBE2C expression data from over 7400 samples from 25 different tumor types deposited in the The Cancer Genome Atlas (TCGA) database and detected a positive correlation between the expressions of the two genes in all tumor types analyzed (Table 1)
Summary
Forkhead box protein M1 (FOXM1) is one of the most studied members of the FOX transcriptional regulators family [1], characterized by an evolutionary conserved ‘forkhead’ or ‘winged-helix’DNA-binding domain (DBD) [2]. FOXM1 functions as an oncogene, contributing, among other processes, to the loss of control of cell cycle progression and cell proliferation, since this protein is a key regulator for G1/S and G2/M transition and M phase progression. The main mechanism by which FOXM1 controls these cellular features is through the transcriptional regulation of key genes involved in cell cycle control [7]. As a member of the anaphase promoting complex/cyclosome (APC/C), ubiquitin conjugating enzyme E2 (UBE2C) promotes the degradation of several target proteins along cell cycle progression, mitotic cyclins, during metaphase/anaphase transition [8,9]. A positive correlation between UBE2C and FOXM1 gene expression in esophageal adenocarcinoma (EAC) samples and in vitro EAC-derived cells was reported [11]
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