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

• Published in: Scientific reports Vol. 7; no. 1; pp. 17289 - 15
• 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: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.12.2017; Nature Publishing Group UK
• Subjects: 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; Humans; Immunoprecipitation; Immunoregulation; Lymphocytes T; Promoter Regions, Genetic; Regulatory sequences; Response Elements; 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 cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in T cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating T cells (CD4 CD25 CD127 ), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating T 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 cells. Chromatin immunoprecipitation analyses of male blood T 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 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 cell physiology.