The Novel Methylation Biomarker NPY5R Sensitizes Breast Cancer Cells to Chemotherapy.

Jiazhou Liu,Guosheng Ren,Yuxian Wei,Lu Gan,Jie Li,Huimin Du,Jing Huang,Yuru Chen,Hongzhong Li,Jiazheng Sun,Xiaoyu Wang,Zhu Qiu

doi:10.3389/fcell.2021.798221

Abstract

Breast cancer (BC) is the most common tumor in women, and the molecular mechanism underlying its pathogenesis remains unclear. In this study, we aimed to investigate gene modules related to the phenotypes of BC, and identify representative candidate biomarkers for clinical prognosis of BC patients. Using weighted gene co-expression network analysis, we here identified NPY5R as a hub gene in BC. We further found that NPY5R was frequently downregulated in BC tissues compared with adjacent tumor-matched control tissues, due to its aberrant promoter CpG methylation which was confirmed by methylation analysis and treatment with demethylation agent. Higher expression of NPY5R was closely associated with better prognosis for BC patients. Gene set enrichment analysis showed that transcriptome signatures concerning apoptosis and cell cycle were critically enriched in specimens with elevated NPY5R. Ectopic expression of NPY5R significantly curbed breast tumor cell growth, induced cell apoptosis and G2/M arrest. Moreover, NPY5R also promoted the sensitivity of BC cells to doxorubicin. Mechanistically, we found that NPY5R restricted STAT3 signaling pathway activation through interacting with IL6, which may be responsible for the antitumor activity of NPY5R. Collectively, our findings indicate that NPY5R functions as a tumor suppressor but was frequently downregulated in BC.

Highlights

Breast cancer (BC) is one of the most common malignant tumors in women, which seriously affects women’s physical and mental health (Sung et al, 2021)
To dig out relevant genes contributing potentially to the pathogenesis of BC, we analyzed the The Cancer Genome Atlas (TCGA)-Breast Invasive Carcinoma (BRCA) and GSE29431 datasets to examine differentially expressed genes (DEGs). 3381 and 1445 DEGs were extracted from the expression profiles in the two datasets, respectively (Supplementary Figures S1A,B)
Since IL6 is a putative activator of STAT3 pathway, we examined if NPY5R can interfere with IL6-mediated activation of STAT3

Summary

Introduction

Breast cancer (BC) is one of the most common malignant tumors in women, which seriously affects women’s physical and mental health (Sung et al, 2021). Its morbidity and mortality have long occupied the first place among female malignant tumors. Treatments based on molecular subtype have achieved striking breakthrough in BC, there are still many patients suffering from recurrence and metastasis, leading to unsatisfactory long-term survival (Desantis et al, 2014). Neuropeptide Y receptor type 5 (NPY5R) is a G-protein coupled receptor which belongs to the subfamily of neuropeptide Y (NPY) receptors mediating the action of endogenous NPY (Kumar et al, 2016). NPY5R is located on human chromosome 4q31-q32 region, encoding 456

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