PUS1 is a novel biomarker for predicting poor outcomes and triple-negative status in breast cancer

Abstract

Breast cancer patients’ outcomes have improved dramatically in recent years, but relapses and poor prognosis remain common due to its aggressiveness and heterogeneity. The development of reliable biomarkers is still needed for predicting prognosis and treatment effectiveness. Recently, a growing body of research suggests that pseudouridine synthases contribute to the development of many cancers, but their contribution to breast cancer remains largely unknown. Using an integrative analysis, we selected pseudouridine synthase1(PUS1) as the candidate biomarker. A tissue microarray of 131 breast cancer patients was then utilized to determine the clinical significance and prognostic value of PUS1. RNA sequencing analysis was conducted to identify downstream genes that differ between control and PUS1 knockdown cells. The effect of PUS1 on phenotypes of cells was assessed using cell proliferation, colony formation, and transwell invasion assays. We found that breast tumors overexpressed PUS1 compared with paired normal tissues. PUS1 expression was positively correlated with triple-negative breast cancer (TNBC) status (P= 0.020) and tumor grade (P <0.0001), but not with age (P= 0.736), tumor size (P= 0.608), lymph node (P= 0.742), oestrogen receptor (ER) (P= 0.162), progesterone receptor (PR) (P= 0.901), human epidermal growth factor receptor 2 (HER2) (P= 0.608) or tumor stage (P= 0.411). Comparatively, patients with high PUS1 levels had shorter overall survival time (P=0.0001) and relapse-free survival time (P = 0.0093). A univariate and multivariate survival analysis suggested that the overall survival of patients was independently influenced by the PUS1 score (Univariate Cox P <0.0001, HR=5.176, 95% CI =2.420-11.07; Multivariate Cox P = 0.001, HR = 5.291, 95% CI =1.893-14.78). RNA sequencing data revealed the PUS1 knockdown significantly affects a series of cancer related biological process such as regulation of cell proliferation and cell migration, as well as KEGG pathways including Mitophagy and PI3K-Akt signaling. In vitro, knockdown of PUS1 significantly suppressed the proliferation and colony formation abilities of MDA-MB-231 cells and BT-549 cells. Additionally, the ability of tumor cells to invade was remarkably attenuated in low PUS1 expression groups compared with the corresponding control groups. Our results suggested that PUS1 is a novel biomarker that predicts poor outcomes in patients with breast cancer and may prove to be a promising treatment target.

Multiomics and machine learning-based analysis of pseudouridine modifications in pan-cancer

“…In addition, inhibition of DKC1 induced telomere-associated senescence and apoptosis in lung adenocarcinoma cells (Kan et al, 2021b). PUS1 knockdown signi cantly affects a range of cancerrelated biological processes, such as the regulation of cell proliferation and cell migration, including mitochondrial autophagy and PI3K-Akt signaling (Fang et al, 2022). PUS7 promotes CRC cell proliferation by activating the Wnt/β pathway through direct stabilisation of SIRT1.…”

RNA epigenetic modifications in ovarian cancer: The changes, chances, and challenges

“…The first is catalyzed by pseudouridine synthases (PUSs) without a template strand, called RNA‐independent pseudouridylation; the second depends on the box H/ACA small ribonucleoprotein RNA‐protein complex, which is known as RNA‐dependent pseudouridylation (Nombela et al, 2021). PUSs such as DKC1, PUS1, PUS7, and PUS10 have adverse effects on different diseases (Cui et al, 2021; Fang et al, 2022; Jana et al, 2017; Mitchell et al, 1999). PUS7 inhibitors, which prevent tRNA pseudouridylation and inhibit tumorigenesis, are potential therapeutic candidates for glioblastoma multiforme (GBM; Cui et al, 2021).…”

PUS1 is a novel biomarker for evaluating malignancy of human renal cell carcinoma

“…As an important member belonging to the pseudouridine synthase family, PUS1 is found to participate in regulating the pseudouridylation modification of almost all kinds of RNAs, including tRNAs, ncRNAs, mRNAs, snoRNAs, and snRNAs [ 16 , 17 ]. Despite its role in various diseases such as myopathy, lactic acidosis and sideroblastic anaemia (MLASA) syndrome [ 18 , 19 ] where PUS1 gene is mutated, recent studies additionally elucidated the versatile role of PUS1 in cancer.…”

“…Despite its role in various diseases such as myopathy, lactic acidosis and sideroblastic anaemia (MLASA) syndrome [ 18 , 19 ] where PUS1 gene is mutated, recent studies additionally elucidated the versatile role of PUS1 in cancer. In a latest report, PUS1 expression was shown to be positively correlated with triple-negative breast cancer (TNBC) status and tumor grade, and thereby can be potentially applied for predicting poor outcomes and triple-negative status in breast cancer [ 16 ].…”