PCLAF promotes neuroblastoma G1/S cell cycle progression via the E2F1/PTTG1 axis

Xiaowei Liu,Cheng Cheng,Xiaoxiao Hu,Zhixiang Wu,Yeming Wu,Yaoyao Gu,Yuanxia Cai,Kai Chen

doi:10.1038/s41419-022-04635-w

Abstract

PCLAF (PCNA clamp-associated factor), also known as PAF15/ KIAA0101, is overexpressed in most human cancers and is a predominant regulator of tumor progression. However, its biological function in neuroblastoma remains unclear. PCLAF is extremely overexpressed in neuroblastoma and is associated with poor prognosis. Through the analysis of various data sets, we found that the high expression of PCLAF is positively correlated with increased stage and high risk of neuroblastoma. Most importantly, knocking down PCLAF could restrict the proliferation of neuroblastoma cells in vitro and in vitro. By analyzing RNA-seq data, we found that the enrichment of cell cycle-related pathway genes was most significant among the differentially expressed downregulated genes after reducing the expression of PCLAF. In addition, PCLAF accelerated the G1/S transition of the neuroblastoma cell cycle by activating the E2F1/PTTG1 signaling pathway. In this study, we reveal the mechanism by which PCLAF facilitates cell cycle progression and recommend that the PCLAF/E2F1/PTTG1 axis is a therapeutic target in neuroblastoma.

Highlights

Neuroblastoma, a malignant tumor originating in the sympathetic nervous system, is the most common extracranial tumor in childhood [1,2,3]
We demonstrated that PCLAF is highly expressed in neuroblastoma, which can accelerate neuroblastoma cell proliferation and cell cycle progression and restrain cell apoptosis, and is related to the poor prognosis of patients
We found that the mRNA level of PTTG1 significantly reduced after silencing PCLAF, indicating that the was most significantly decreased expression of PCLAF could inhibit the proliferation of decreased after PCLAF expression was downregulated (Fig. 4A, neuroblastoma cells (Fig. 2D, E)

Summary

INTRODUCTION

Neuroblastoma, a malignant tumor originating in the sympathetic nervous system, is the most common extracranial tumor in childhood [1,2,3]. Treatment strategies for neuroblastoma are tailored according to the risk classification of the disease as well as clinical and tumor biological markers [6]. Comprehending the underlying molecular biological mechanisms of neuroblastoma is indispensable for exploring up-and-coming strategies to enhance prognostic stratification and further ameliorate the prognosis of patients. PCLAF is one such cofactor and can regulate the binding of DNA polymerase and PCNA [10, 11]. We demonstrated that PCLAF is highly expressed in neuroblastoma, which can accelerate neuroblastoma cell proliferation and cell cycle progression and restrain cell apoptosis, and is related to the poor prognosis of patients. Our analysis of neuroblastoma databases and clinical tissue samples confirmed that PCLAF showed a significantly positive correlation with PTTG1. We clarify the existence of the PCLAF/E2F1/PTTG1 axis, which has an imperative role in cell cycle progression in neuroblastoma cells

MATERIALS AND METHODS

Liu et al 3

DISCUSSION

Findings

ETHICS STATEMENT