HOTAIR promotes paclitaxel resistance by regulating CHEK1 in ovarian cancer

Abstract

Purpose

The HOX transcript antisense RNA (HOTAIR) has been reported to be aberrantly expressed in ovarian cancer (OC). Abnormal high expression level of HOTAIR has been found to be associated with poor overall survival of OC patients. Yet, the role of HOTAIR in paclitaxel resistance of OC is unclear. This study aims to investigate the effect, as well as the mechanism of HOTAIR in promoting paclitaxel resistance of OC.

Methods

Ovarian cancer cell lines with down-regulated and up-regulated expression of HOTAIR were, respectively, established. The expression of HOTAIR was confirmed by qRT-PCR. The sensitivity of ovarian cancer cells to paclitaxel was detected by MTT assays, colony formation, EdU assays, flow cytometry, and in vivo experiments.

Results

An increased expression level of HOTAIR was observed in ovarian cancer cell lines following treatment with paclitaxel. When the expression of HOTAIR was down-regulated, the proliferation of ovarian cancer cells was found to be inhibited, coupled with enhanced cell sensitivity to paclitaxel. Conversely, when the HOTAIR expression was up-regulated, an opposite effect was observed on the ovarian cancer cells. In addition, cell cycle arrest in G2/M phase was also shown to be accelerated upon HOTAIR suppression. Strikingly, our results also revealed that HOTAIR plays a regulatory role in the expression of checkpoint kinase 1 (CHEK1), and that the restored paclitaxel sensitivity through knockdown of HOTAIR can be weakened by CHEK1 up-regulation. Consistently, in vivo data confirmed that the therapeutic efficacy of paclitaxel can be enhanced through down-regulation of HOTAIR, and that CHEK1 is the down-stream target of HOTAIR in inducing paclitaxel resistance.

Conclusion

HOTAIR confers paclitaxel resistance in epithelial ovarian cancer by increasing the protein level of CHEK1.

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Availability of data and materials

The datasets used and/or analyzed in this study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81602277) and the Natural Science Foundation of Hubei Province (No. 2018CFB557).

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Correspondence to Xiaoqi He or Chun Yang.

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Cite this article

Jiang, J., Wang, S., Wang, Z. et al. HOTAIR promotes paclitaxel resistance by regulating CHEK1 in ovarian cancer. Cancer Chemother Pharmacol (2020). https://doi.org/10.1007/s00280-020-04120-1

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Keywords

  • CHEK1
  • Drug resistance
  • HOTAIR
  • Ovarian cancer
  • Paclitaxel