SNRPD1 confers diagnostic and therapeutic values on breast cancers through cell cycle regulation

Xiaofeng Dai,Xiao Chen,Jianying Zhang,Lihui Yu

doi:10.1186/s12935-021-01932-w

Abstract

BackgroundSNRPD1 is a spliceosome-associated protein and has previously been implicated with important roles in cancer development.MethodsThrough analyzing the differential expression patterns and clinical association of splicing associated genes among tumor and tumor adjacent samples across different tumors and among different breast cancer subtypes, we identify the tumor promotive role of SNRPD1 using multiple publicly available datasets. Through pathway, gene ontology enrichment analysis and network construction, we linked the onco-therapeutic role of SNRPD1 with cell cycle. Via a series of experimental studies including knockdown assay, qPCR, western blotting, cell cycle, drug response assay, we confirmed the higher expression of SNPRD1 at both gene and protein expression levels in triple negative breast cancer cells, as well as its roles in promoting cell cycle and chemotherapy response.ResultsOur study revealed that SNRPD1 over-expression was significantly associated with genes involved in cell cycle, cell mitosis and chromatin replication, and silencing SNRPD1 in breast cancer cells could lead to halted tumor cell growth and cell cycle arrest at the G0/G1 stage. We also found that triple negative breast cancer cells with reduced SNRPD1 expression lost certain sensitivity to doxorubicin whereas luminal cancer cells did not.ConclusionsOur results suggested the prognostic value of SNRPD1 on breast cancer survival, its potential as the therapeutic target halting cell cycle progression for breast cancer control, and warranted special attention on the combined use of doxorubicin and drugs targeting SNRPD1.

Highlights

Spliceosome is a dynamic complex that catalyzes the splicing of precursor RNA into mRNA in eukaryotic cells and comprised of 5 small nuclear ribonucleoproteins, i.e., U1, U2, U4, U5, U6, and more than 200 polypeptides [1, 2]
Basal breast cancer cells are the counterpart of Triple negative breast cancers (TNBCs) at the cell line level, which showed higher SNRPD1 expression than non-basal cells according to the CLM cell line gene expression data (p < 2E−16, Fig. 2c)
Receiver operating characteristic (ROC) curves showed the performances of SNRPD1 and KI67 in prognosing triple negative breast cancers (AUC = 0.82 for SNRPD1, AUC = 0.8 for KI67, Fig. 2g)

Summary

Introduction

Spliceosome is a dynamic complex that catalyzes the splicing of precursor RNA into mRNA in eukaryotic cells and comprised of 5 small nuclear ribonucleoproteins (snRNPs), i.e., U1, U2, U4, U5, U6, and more than 200 polypeptides [1, 2]. We analyzed the transcriptomic profiles of the 7 core Sm proteins across 31 cancer types and among breast cancer subtypes, and found that SNRPD1 had the highest number of cancers with over 2 folds up-regulation between cancer and normal tissues (Table 1), and the distribution of SNPRD1 could be nicely split into two. Spliceosome assembly components were revealed as the most enriched pathway deregulated in breast cancers with SNRPD1 being an important player according to exonic expression profiling of 120 breast tumors and 45 benign lesions [13]. SNRPD1 over-expression was used to define subsets of highly aggressive cancers [15] and was proposed as therapeutic targets of multiple cancers such as melanoma, lung and breast tumor cells as a result of induced autophagy [15]. SNRPD1 is a spliceosome-associated protein and has previously been implicated with important roles in cancer development

Methods

Results

Discussion

Conclusion