Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer

• Published in: Scientific reports 2017-12, Vol.7 (1), p.17289-15, Article 17289
• Main Authors: Adurthi, Sreenivas, Kumar, Mahesh M., Vinodkumar, H. S., Mukherjee, Geetashree, Krishnamurthy, H., Acharya, K. Kshitish, Bafna, U. D., Uma, Devi K., Abhishekh, B., Krishna, Sudhir, Parchure, A., Alka, Murali, Jayshree, R. S.
• Format: Article
• Language: English
• Subjects: 631/250/580; 692/4028/67/580; 82; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CD25 antigen; CD4 antigen; Cervical cancer; Cervix; Chromatin; Computer applications; Deoxyribonucleic acid; DNA; Estradiol - metabolism; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Immunoprecipitation; Immunoregulation; Lymphocytes T; multidisciplinary; Promoter Regions, Genetic; Regulatory sequences; Response Elements; Science; Science (multidisciplinary); Signal Transduction; T-Lymphocytes, Regulatory - immunology; Tumor Cells, Cultured; Tumors; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-17102-w

Oestrogen controls Foxp3 expression in regulatory T cells (T reg cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in T reg cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating T reg cells (CD4 + CD25 hi CD127 low ), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating T reg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERα complexes to FOXP3 protein in CxCa-derived T reg cells. Chromatin immunoprecipitation analyses of male blood T reg cells revealed ERα occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ERα signalling is critical for the sustenance of FOXP3 expression and T reg cell function in human CxCa via direct interaction of ERα with FOXP3 promoter. Overall, our work gives a molecular insight into ERα signalling and highlights a fundamental role of E2 in controlling human T reg cell physiology.