Knockdown of long non-coding RNA HOTAIR reverses cisplatin resistance of ovarian cancer cells through inhibiting miR-138-5p-regulated EZH2 and SIRT1

Abstract

Background: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. Methods: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. Results: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. Conclusions: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

“…It, in turn, can directly regulate the expression of EZH2 and SIRT1, which have been proven to be involved in the regulation of cisplatin resistance in ovarian cancer [ 161 ]. In addition, other miRNAs (such as miR-34a and miR-454) can be involved in regulating the chemosensitivity of ovarian cancer through the functional interaction with HOTAIR [ 118 ]. HOTAIR plays an important oncogenic role in cervical cancer, promoting the proliferation, migration, and invasion of cancer cells.…”

LncRNAs in Ovarian Cancer Progression, Metastasis, and Main Pathways: ceRNA and Alternative Mechanisms

“…The axis HOTAIR/miR-200c/SNAIL (or SNAI1, zinc finger transcription factor), involved in OvCa invasion, was demonstrated using transduced lentivirus-miR-200c, gain- or loss-of-function assays, EMT markers, and tumorigenicity of SKOV3 cells in xenograft tumor studies [ 118 ]. In recent work, it was shown that miR-138-5p could directly bind to HOTAIR and 3’-UTR of EZH2 (enhancer of zeste homolog 2, a histone-lysine N-methyltransferase) and SIRT1 (NAD-dependent deacetylase sirtuin 1), which was validated by the dual-luciferase reporter assay [ 119 ]. Moreover, using cisplatin-resistant OvCa cell lines, it was shown that HOTAIR reduces cisplatin chemosensitivity of OvCa cells via the axis HOTAIR/miR-138-5p/EZH2 (SIRT1) [ 119 ].…”

The Role of Non-Coding RNAs as Prognostic Factor, Predictor of Drug Response or Resistance and Pharmacological Targets, in the Cutaneous Squamous Cell Carcinoma

“…For lncRNA THOR, as well as for LINC00346, there is only one piece of evidence for each which demonstrates that their high expression is linked to a reduced sensitivity to cisplatin due to increased cell stemness for THOR and the inhibition of miR-342-5p for LINC00346 [ 132 , 145 ]. For lncRNA HOTAIR, similar evidence is reported in various tumor pathologies, such as lung cancer via p21 down-regulation and ovarian cancer, by activating the Wnt/b-catenin pathway or inhibiting EZH2 and SIRT1 [ 133 , 134 , 135 , 136 ]. There is no evidence in the literature on the interaction between cisplatin and the other lncRNAs with the role of oncogene reported in Table 3 .…”