HDAC6, modulated by miR-206, promotes endometrial cancer progression through the PTEN/AKT/mTOR pathway

Yawen Zheng,Zhiling Wang,Xingsheng Yang,Chunyan Wang,Meng Li,Xiaojie Wang,Yuanjian Wang,Shuo Zhang,Xiaohui Yang

doi:10.1038/s41598-020-60271-4

Abstract

Endometrial cancer (EC) is the sixth most common cancer in women. Since early EC has a good prognosis, identifying methods for early diagnosis is valuable. Here, we aimed to study the role of HDAC6, which has been indicated important in many kinds of cancers, in EC diagnosis and therapy. First, the expression levels of HDAC6 in EC tissues and cells were measured by qRT-PCR and Western blotting, and through bioinformatics and dual luciferase assays, HDAC6 was found to be a direct target of miR-206. Then, CCK-8, colony formation, wound healing, and Transwell assays were performed; these results indicated that HDAC6 promoted EC cell proliferation, metastasis and invasion, while miR-206 produced the opposite effects. In addition, rescue assays verified that the effect of miR-206 could be reversed by HDAC6, and global gene expression analysis confirmed the relationship between miR-206 and HDAC6. Finally, we measured the levels of PTEN, p-AKT and p-mTOR and other key molecules and speculated that miR-206 might target HDAC6 to suppress EC progression via the PTEN/AKT/mTOR pathway. In conclusion, downregulation of miR-206 and upregulation of HDAC6 in EC may predict poor prognosis, and as the target gene of miR-206, HDAC achieves its carcinogenic effect through the PTEN/AKT/mTOR pathway.

Highlights

Endometrial cancer (EC) is the sixth most general female cancer and the 15th most common cancer overall[1]
UALCAN. (C) quantitative real-time PCR (qRT-PCR) showed higher Histone deacetylase 6 (HDAC6) expression in EC tissues than in paired adjacent normal tissues (n = 46). (D) Western blot analysis showed that cancer tissues expressed more HDAC6 than paracancerous control tissues (n = 46). (E) IHC analysis showed the HDAC6 expression levels in paraffin-embedded normal endometrial and EC specimens (100×, 200×). (F) Western blot analysis showed the HDAC6 expression levels in four selected EC cell lines—HEC-1-A, Ishikawa, AN3C, and
IHC analysis of 36 paraffin-embedded EC tissues and 8 normal endometrial tissues showed that HDAC6 was expressed mainly in the cytoplasm and that the staining intensity increased with increasing tumour grade (Fig. 1E)

Summary

Introduction

Endometrial cancer (EC) is the sixth most general female cancer and the 15th most common cancer overall[1]. Characterized by an oestrogen-related, low-grade phenotype and good prognosis, type I is the most common (85–90%)[3]. For both types, the earlier the diagnosis and intervention, the better are the long-term outcomes. MiR-206 has been shown to be markedly downregulated in many cancers, such as lung cancer, breast cancer, rhabdomyosarcoma and head and neck squamous cell carcinoma[13,14,15,16], but its function in EC is unclear. Our results suggest that miR-206 and HDAC6 play critical roles in EC development and may be innovative diagnostic markers and therapeutic targets for EC

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Results

Conclusion