Histone acetyltransferase CSRP2BP promotes the epithelial–mesenchymal transition and metastasis of cervical cancer cells by activating N-cadherin

Abstract

Abstract Background: Dysregulated epithelial–mesenchymal transition (EMT) is involved in cervical cancer metastasis and is associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. Methods: Here, we systematically investigated the expression patterns of histone acetylation genes and their correlations with EMT pathway in cervical cancer. The expression of histone acetyltransferase CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effect of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were determined by cell growth curve, EdU assay, flow cytometryand xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effect of CSRP2BP on the cellinvasion, metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter were further applied to research for the roles and molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and matastasis. Results: We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effect. In addition, CSRP2BP-promoted resistant to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, and cooperate with the transcription factor SMAD4, bound to the SEB2 domain of the N-cadherin gene promotor region and upregulated N-cadherin transcription. Consequently, CSRP2BP involved cervical cancer cell EMT and matastasis dependent on activating N-cadherin. Conclusions: These findings reveal for the first time the involvement of histone acetyltransferase CSRP2BP in cervical cancer metastasis partially through promoting the EMT process and imply that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.