Abstract
Non-SMC condensin I complex subunit H (NCAPH) is a vital gene associated with chromosome stability and is required for proper chromosome condensation and segregation. However, the mechanisms through which NCAPH affects pancreatic cancer (PC) and its molecular function remain unclear. In this study, we examined the role of NCAPH in PC cells. Our results showed that NCAPH was overexpressed in clinical PC specimens (GEPIA) and cell lines. In addition, in NCAPH-knockdown cells, colony formation and proliferation were inhibited, and the cell cycle was arrested at the S and G2/M phases owing to failure of mature chromosome condensation (MCC) in poorly condensed chromosomes. Increased cell death in NCAPH-knockdown cells was found to help initiate apoptosis through the activation of caspase-3 and PARP cleavage. Furthermore, NCAPH-knockdown cells showed an increase in chromosomal aberrations and DNA damage via activation of the DNA damage response (Chk1/Chk2) signaling pathways. These data demonstrated that NCAPH played an important role in cell cycle progression and DNA damage by maintaining chromosomal stability through progression of MCC from poorly condensed chromosomes. Ultimately, NCAPH knockdown induced apoptotic cell death, which was partially mediated by caspase-dependent pathways. These findings highlight the potential role of NCAPH as a therapeutic target for PC.
Highlights
More than 90% of pancreatic cancer (PC) cases are classified as pancreatic ductal adenocarcinoma (PDA), one of the most lethal human malignant tumors with a poor prognosis[1]
According to the data obtained from TCGA, the expression of NCAPH was significantly higher than that of the condensin subunits in all pancreatic adenocarcinoma (PAAD) tumor types (n = 179) compared with that in their normal tissue counterparts obtained from TCGA and that obtained from GTEx data (n = 171; Fig. 1A and Supplementary Fig. 1A)
The results showed that protein expression of condensin I rather than II was higher in various PC cell lines compared with its expression in human pancreatic duct epithelial (HPDE) cells, and NCAPH was markedly upregulated by approximately 10-fold (Fig. 1B,C, and Supplementary Fig. 1B)
Summary
More than 90% of pancreatic cancer (PC) cases are classified as pancreatic ductal adenocarcinoma (PDA), one of the most lethal human malignant tumors with a poor prognosis[1]. One of the non-SMC subunits of each of the human condensins, NCAPH in condensin I and NCAPH2 in condensin II, belongs to the kleisin family of proteins[11,13] and binds the ATP-binding cassette (ABC)-transporter-like ATPase domains at the other end of the coils[14]. According to a recent study, the Ycg1-Brn[1] (NCAPG/G2-NCAPH/H2) subcomplex of condensin binds directly to DNA and is essential for the stable association of condensin complexes with chromosomes and condensin function[14]. Recent studies have shown that a small fraction of condensin I remains in the nucleus during interphase and plays a role in gene regulation and chromosome condensation[23]. Recent studies have suggested that subunits of condensin complexes I and II can serve as new potential biomarkers and therapeutic targets for some human cancers[25,26,27,28]. In this study, we aimed to evaluate differences in the expression of NCAPH in PC tissues and cell lines compared with that in human pancreatic duct epithelial (HPDE) cells, examined the roles of NCAPH in PC, and assessed the mechanisms through which NCAPH functions in this context
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