ASF1B Promotes Oncogenesis in Lung Adenocarcinoma and Other Cancer Types.

Wencheng Zhang,Zhouyong Gao,Fanjie Meng,Guangshun Wang,Ning Liu,Mingxiu Guan

doi:10.3389/fonc.2021.731547

Abstract

Anti-silencing function 1B histone chaperone (ASF1B) is known to be an important modulator of oncogenic processes, yet its role in lung adenocarcinoma (LUAD) remains to be defined. In this study, an integrated assessment of The Cancer Genome Atlas (TCGA) and genotype-tissue expression (GTEx) datasets revealed the overexpression of ASF1B in all analyzed cancer types other than LAML. Genetic, epigenetic, microsatellite instability (MSI), and tumor mutational burden (TMB) analysis showed that ASF1B was regulated by single or multiple factors. Kaplan-Meier survival curves suggested that elevated ASF1B expression was associated with better or worse survival in a cancer type-dependent manner. The CIBERSORT algorithm was used to evaluate immune microenvironment composition, and distinct correlations between ASF1B expression and immune cell infiltration were evident when comparing tumor and normal tissue samples. Gene set enrichment analysis (GSEA) indicated that ASF1B was associated with proliferation- and immunity-related pathways. Knocking down ASF1B impaired the proliferation, affected cell cycle distribution, and induced cell apoptosis in LUAD cell lines. In contrast, ASF1B overexpression had no impact on the malignant characteristics of LUAD cells. At the mechanistic level, ASF1B served as an indirect regulator of DNA Polymerase Epsilon 3, Accessory Subunit (POLE3), CDC28 protein kinase regulatory subunit 1(CKS1B), Dihydrofolate reductase (DHFR), as established through proteomic profiling and Immunoprecipitation-Mass Spectrometry (IP-MS) analyses. Overall, these data suggested that ASF1B serves as a tumor promoter and potential target for cancer therapy and provided us with clues to better understand the importance of ASF1B in many types of cancer.

Highlights

Lung cancer is one of the most common and deadliest forms of malignant cancer throughout the world [1]
We began by querying the genotype-tissue expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, revealing pronounced Anti-silencing function 1B histone chaperone (ASF1B) upregulation in all cancers other than Acute
We found that ASF1B expression levels varied significantly among different clinical stages in patients with Adrenocortical carcinoma (ACC), Breast invasive carcinoma (BRCA), Colon adenocarcinoma (COAD), Kidney Chromophobe (KICH), Kidney renal clear cell carcinoma (KIRC), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC) and Skin Cutaneous Melanoma (SKCM) (Figure 1C)

Summary

Introduction

Lung cancer is one of the most common and deadliest forms of malignant cancer throughout the world [1]. Genetic mutation is the primary process that drives oncogenesis [4, 5], with gene-specific overexpression or silencing being associated with epigenetic mechanisms such as changes in histone posttranslational modification or DNA methylation [6,7,8]. Histone H3–H4 chaperone anti-silencing function 1 (ASF1) is a key histone chaperone involved in regulating processes including DNA replication, DNA damage repair, and transcription [12, 13]. There are two paralogous forms of ASF1: Anti-Silencing Function 1A Histone Chaperone (ASF1A) and ASF1B. Increased ASF1B expression levels have been linked to the prognosis of LUAD and breast cancer patients [15, 16]. We examined the impact of knocking down and overexpressing ASF1B on proliferation, cell cycle progression, apoptosis, and potential mechanism of LUAD. Our data provide novel insights into the functional importance of ASF1B in LUAD and indicate ASF1B as a potential target for the therapeutic management of cancers

Methods

Results

Conclusion