CENPA facilitates hepatocellular carcinoma proliferation by cooperating with YY1 to drive transcription of CCND1 and NRP2.

Abstract

Abstract Background The centromere proteins (CENPs) are the key regulators in mitosis-related protein complexes and involved in kinetochore assembly and chromosome segregation during mitosis, yet they remain largely unexplored in hepatocellular carcinoma (HCC). Methods In our study, we analyzed the potential role of CENPs family numbers by bioinformatic analysis. We detected the expression level of Centromere protein A (CENPA) in HCC tissues and cells by qRT-PCR, IHC and western blotting. Furthermore, CCK-8, colony formation, EdU and flow cytometry assays were used to evaluated the potential function of CENPA in HCC cells. Subcutaneous and orthotopically mouse model were used to explored the oncogenic role of CENPA. Besides, we demonstrated the interaction between CENPA and YY1 by silver staining and co-immunoprecipitation (co-IP) assays. Dual luciferase reporter and ChIP-sequencing (ChIP-seq) assays were used to identify the potential binding sites of CENPA and YY1 on CCND1 and NRP2 promoter regions. Results In this study, CENPA was identified significantly up-regulated in HCC, and the CENPA overexpression was linked to the poor prognosis of HCC patients. CENPA knockdown inhibited the HCC cell proliferation and tumor growth. Mechanistically, CENPA activated YY1 transcription and cooperatively interacted with YY1 to bind at cyclin D1 (CCND1) and neuropilin 2 (NRP2) promoter regions for transcriptional activation. Moreover, we identified a lactylation modification site (K124) of CENPA, which is essential for CENPA to activate its target genes transcriptionally. Conclusions These findings indicate the synergistic mechanism between CENPA and YY1 that promotes CCND1 and NRP2 expression, which leads to HCC progression.