Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells

• Published in: Oncogene Vol. 27; no. 1; pp. 9 - 19
• Main Authors: Goto, T., Takano, M., Albergaria, André, Briese, J., Pomeranz, K. M., Cloke, B., Fusi, L., Feroze-Zaidi, F., Maywald, N., Sajin, M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 03-01-2008; Nature Publishing Group UK; Nature Publishing
• Subjects: Apoptosis; Biological and medical sciences; Cancer; Cancer cells; Carcinoma; Carcinoma, Endometrioid - drug therapy; Carcinoma, Endometrioid - genetics; Carcinoma, Endometrioid - metabolism; Carcinoma, Endometrioid - pathology; Cell Biology; Cell Line; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; DNA binding proteins; Down-Regulation - genetics; Down-Regulation - physiology; Drug Resistance; Drug Resistance, Neoplasm - genetics; Endometrial cancer; Endometrial Neoplasms; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrioid; Female; Female genital diseases; Forkhead Box Protein O1; Forkhead Transcription Factors; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - deficiency; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; FOXO1; Fundamental and applied biological sciences. Psychology; GADD45 alpha; GADD45alfa; Gene expression; Gene Expression Regulation; Gene Expression Regulation, Neoplastic - physiology; Genetic aspects; Genetics; Genomic Instability; Genomic Instability - genetics; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Molecular genetics; Neoplasm; Neoplastic; Oncology; original-article; Paclitaxel; Physiological aspects; Science & Technology; Signal transduction; Transcription; Transcription. Transcription factor. Splicing. Rna processing; Tumor; Tumors; United Kingdom; GADD45; endometrial cancer; phosphatidylinositol-3 kinase/Akt; paclitaxel; transcription; FOXO1; Antineoplastic agent; Endometrium cancer; Transcription; Enzyme; GADD45a; Transferases; Akt protein kinase; Malignant tumor; Gene expression; Carcinogenesis; Mechanism; Female genital diseases; 1-Phosphatidylinositol 3-kinase; Paclitaxel; Uterine diseases; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210626

The forkhead transcription factor FOXO1, a downstream target of phosphatidylinositol-3-kinase/Akt signalling pathway, regulates cyclic differentiation and apoptosis in normal endometrium, but its role in endometrial carcinogenesis is unknown. Screening of endometrial cancer cell lines demonstrated that FOXO1 is expressed in HEC-1B cells, but not in Ishikawa cells, which in turn highly express the FOXO1 targeting E3-ubiquitin ligase Skp2. FOXO1 transcript levels were also lower in Ishikawa cells and treatment with the proteasomal inhibitor was insufficient to restore expression. Lack of FOXO1 expression in Ishikawa cells was not accounted for by differential promoter methylation or activity, but correlated with increased messenger RNA (mRNA) turnover. Comparative analysis demonstrated that HEC-1B cells proliferate slower, but are more resistant to paclitaxel-mediated cell death than Ishikawa cells, which were partially reversed upon silencing of FOXO1 in HEC-1B cells or its re-expression in Ishikawa cells. We further show that FOXO1 is required for the expression of the growth arrest- and DNA-damage-inducible gene GADD45alpha. Analysis of biopsy samples demonstrated a marked loss of FOXO1 and GADD45alpha mRNA and protein expression in endometrioid endometrial cancer compared to normal endometrium. Together, these observations suggest that loss of FOXO1 perturbs endometrial homeostasis, promotes uncontrolled cell proliferation and increases susceptibility to genotoxic insults.
This work was financially supported by the Great Britain Sasakawa Foundation and the IOG Trust.