Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors

Abstract

Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G 2 /M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.

Altered Expression of the Early Mitotic Checkpoint Protein, CHFR, in Breast Cancers: Implications for Tumor Suppression

“…Therefore, CHFR has been hypothesized to be a tumor suppressor with a potential role as a biomarker for chemotherapeutic response to Taxol (4,5). Many reports have noted that cancer cells that have lost CHFR expression are more likely to undergo apoptosis in response to microtubule poisons, which strongly supports this hypothesis (1,(5)(6)(7). The molecular mechanism by which CHFR initiates a cell cycle arrest is debated, although evidence implicates the p38/mitogen-activated protein kinase pathway, an Aurora A interaction, and/or through regulation of PLK-1 (8)(9)(10)(11).…”

Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer

“…A previous study has also reported that sensitivity to CDDP in endometrial cancer cells with CHFR methylation was unaltered after demethylation, whereas sensitivity to PTX decreased after demethylation, 19 while another study found no correlation between CHFR methylation and sensitivity to CDDP or VP-16 through experiments with cancer cell lines. 20 We also showed that CHFR methylation status did not affect sensitivity to other anticancer agents such as CDDP, CBDCA, GEM, VNR, CPT-11 or VP-16 (Fig. 3).…”

CHFR Promoter Methylation Indicates Poor Prognosis in Stage II Microsatellite Stable Colorectal Cancer

“…This eventually results in cell-cycle arrest and a less invasive phenotype (58). In addition to a potential role for CHFR as prognostic biomarker, CHFR promoter methylation has been proposed as biomarker for response to microtubule inhibitor taxanes in endometrial (59), cervical (59), oral (60), and gastric cancer (61). Although taxanes are not implemented in CRC treatment because they failed to demonstrate a significant clinical benefit in phase II trials (62), CRCs with CHFR promoter methylation might benefit from taxanes.…”