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

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.

SUBMITTER: Liu X

PROVIDER: S-EPMC8873510 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Liu Xiaowei X Cai Yuanxia Y Cheng Cheng C Gu Yaoyao Y Hu Xiaoxiao X Chen Kai K Wu Yeming Y Wu Zhixiang Z

Cell death & disease 20220224 2

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, k ...[more]

PMID: 35210406

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Project description:BackgroundE2F1 is a transcription factor that regulates cell cycle progression. It is highly expressed in most cancer cells and activates transcription of cell cycle-related kinases. Stathmin1 and transforming acidic coiled-coil-containing protein 3 (TACC3) are factors that enhance the stability of spindle fiber.MethodsThe E2F1-mediated transcription of transforming acidic coiled-coil-containing protein 3 (TACC3) and stathmin1 was examined using the Cancer Genome Atlas (TCGA) analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, chromatin immunoprecipitation (ChIP), and luciferase reporter. Protein-protein interaction was studied using co-IP. The spindle structure was shown by immunofluorescence. Phenotype experiments were performed through MTS assay, flow cytometry, and tumor xenografts. Clinical colorectal cancer (CRC) specimens were analyzed based on immunohistochemistry.ResultsThe present study showed that E2F1 expression correlates positively with the expression levels of stathmin1 and TACC3 in colorectal cancer (CRC) tissues, and that E2F1 transactivates stathmin1 and TACC3 in CRC cells. Furthermore, protein kinase A (PKA)-mediated phosphorylation of stathmin1 at Ser16 is essential to the phosphorylation of TACC3 at Ser558, facilitating the assembly of TACC3/clathrin/α-tubulin complexes during spindle formation. Overexpression of Ser16-mutated stathmin1, as well as knockdown of stathmin1 or TACC3, lead to ectopic spindle poles including disorganized and multipolar spindles. Overexpression of wild-type but not Ser16-mutated stathmin1 promotes cell proliferation in vitro and tumor growth in vivo. Consistently, a high level of E2F1, stathmin1, or TACC3 not only associates with tumor size, lymph node metastasis, TNM stage, and distant metastasis, but predicts poor survival in CRC patients.ConclusionsE2F1 drives the cell cycle of CRC by promoting spindle assembly, in which E2F1-induced stathmin1 and TACC3 enhance the stability of spindle fiber.

Dataset Information

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

Publications

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

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