HDAC6 suppresses microRNA-199a transcription and augments HPV-positive cervical cancer progression through Wnt5a upregulation.

Abstract High-risk human papillomavirus (HR-HPV) infection is a major risk factor for the initiation and progression of cervical cancer (CC). This study aimed to explore the relevance of histone deacetylase 6 (HDAC6) in HPV-positive CC and the molecules implicated. Differentially expressed genes between HPV-positive and HPV-negative tissues, and differentially expressed microRNAs (miRNAs) in cells after HDAC6 downregulation were identified using microarray analyses. The expression profiles of HDAC6 and miR-199a and their cellular functions were investigated via loss-of-function studies. Xenograft tumors were induced in mice for in vivo studies. HDAC6 and Wnt5a were highly expressed, whereas miR-199a was poorly expressed in HPV-positive CC tissues. Downregulation of HDAC6 reduced proliferation, migration, invasion, and resistance to apoptosis of HPV-positive CC cells. HDAC6 suppressed the transcription of miR-199a, and miR-199a targeted Wnt5a to inactivate the Wnt signaling pathway. Further downregulation of miR-199a blocked the inhibitory effect of HDAC6 silencing on CC cell growth both in vivo and in vitro, whereas further artificial inhibition of Wnt5a reduced Wnt signaling and blocked the malignant behavior of CC cells. This study showed that HDAC6 suppresses the transcription of miR-199a and enhances the progression of HPV-positive cervical cancer through upregulation of Wnt5a.