HOXA5 inhibits the proliferation and neoplasia of cervical cancer cells via downregulating the activity of the Wnt/β-catenin pathway and transactivating TP53

• Published in: Cell death & disease 2020-06, Vol.11 (6), p.420, Article 420
• Main Authors: Ma, Hong-Mei, Cui, Nan, Zheng, Peng-Sheng
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/31; 13/95; 38; 38/47; 38/91; 631/67/1517/1371; 631/80/304; 82; 82/80; 96/44; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Biology; Cell Culture; Cell cycle; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell viability; Cervical cancer; Cervical carcinoma; Cervix; Chromatin; Cyclin D1 - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Down-Regulation - genetics; Ectopic expression; Embryogenesis; Female; Gene Expression Regulation, Neoplastic; Gene set enrichment analysis; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Immunohistochemistry; Immunology; Immunoprecipitation; Life Sciences; Mice, Inbred BALB C; Mice, Nude; Models, Biological; p53 Protein; Promoter Regions, Genetic - genetics; Ribonucleic acid; RNA; S phase; Transcriptional Activation - genetics; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Up-Regulation - genetics; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Wnt protein; Wnt Signaling Pathway - genetics; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2629-3

HOXA5 is considered a regulator involved in embryonic development and cellular differentiation and a tumor suppressor. Nevertheless, its biological role in cervical carcinoma is still unclear. In the present study, immunohistochemistry showed that HOXA5 expression gradually decreased as the degree of cervical lesions deepened. Ectopic expression of HOXA5 restrained cell proliferation, decreased cell viability, and inhibited tumor formation in vitro and in vivo. Furthermore, the expression of HOXA5 could arrest cell cycle from G0/G1 to S phase. RNA-seq revealed that p21 and cyclinD1 were involved in this process. Moreover, the gene set enrichment analysis and the TOP/FOP reporter assay both suggested that HOXA5 could restrain the activity of the Wnt/β-catenin pathway. Further study using dual-luciferase reporter assay and quantitative chromatin immunoprecipitation assay demonstrated that HOXA5 could directly bind to the TAAT motif within the promoter of TP53 by its HD domain and transactivate TP53, which can upregulate p21. Altogether, our data suggest that HOXA5 inhibits the proliferation and neoplasia via repression activity of the Wnt/β-catenin pathway and transactivating TP53 in cervical cancer.