ASF1a inhibition induces p53-dependent growth arrest and senescence of cancer cells

Yujiao Wu,Xidan Li,Jingya Yu,Dawei Xu,Magnus Björkholm

doi:10.1038/s41419-019-1357-z

Abstract

Anti-silencing function 1a (ASF1a) is a histone H3–H4 chaperone isoform involved in chromatin assembling and transcription regulation. Recently, ASF1a has been shown to be up-regulated in certain human malignancies and required for the expression of telomerase reverse transcriptase (TERT), a factor essential for the immortal phenotype of cancer cells; however, its role in oncogenesis remains poorly defined. In the present study, we determine whether ASF1a is required for the unlimited proliferation of cancer cells, a key cancer hallmark. Elevated ASF1a mRNA expression was observed in hepatocellular carcinoma (HCC) tumors. The overexpression of ASF1a was similarly found in 20 cancer types contained in TCGA and GTEx datasets. ASF1a knockdown led to growth arrest and senescence of wild-type (wt) p53-carrying HCC and prostate cancer cells. Cellular senescence mediated by ASF1a inhibition resulted from the robust up-regulation of p53 and p21cip1 expression, but without detectable changes in TERT expression. p53 inhibition attenuated p21cip1 induction caused by ASF1a depletion. Mechanistically, ASF1a-knocked down cells displayed widespread DNA damage. The TCGA dataset analysis revealed a negative correlation between ASF1a and p21cip1 expression in multiple types of primary tumors, including HCC, prostate, gastric, and breast cancer. Higher ASF1a and lower p21cip1 expression predicted a poor outcome in patients with HCC. Our results reveal that ASF1a overexpression is widespread in human malignancies and is required for the infinite proliferation of cancer cells, whereas its inhibition induces DNA damage and subsequent up-regulation of p53-p21cip1 expression, thereby triggering cellular senescence. Thus, ASF1a may serve as a potential target in cancer therapy.

Highlights

Anti-silencing function 1 (ASF1), the most conserved histone H3–H4 chaperone, plays an important role in DNA replication, gene expression, DNA repair, and nucleosome assembly[1,2]
(https://cancergenome.nih.gov) and GTEx databases, and the results were documented in Fig. 1b: ASF1a was overexpressed in hepatocellular carcinoma (HCC), prostate cancer (PCa), gastric cancer (GC), and breast cancer (BC) tumor tissues compared with their non-tumorous counterparts
ASF1a cooperates with acetyltransferase CBP/p300 to acetylate H3 at lys[56] position, which is regarded as a marker for chromatin disassembly and active transcription[28]

Summary

Introduction

Anti-silencing function 1 (ASF1), the most conserved histone H3–H4 chaperone, plays an important role in DNA replication, gene expression, DNA repair, and nucleosome assembly[1,2]. ASF1a and ASF1b preserved most of their ancestors' conserved characters while they developed novel and ASF1a may reverse the unlimited proliferation of cancer cells via TERT inhibition. Wu et al Cell Death and Disease (2019)10:76. By limiting the replicative life span of somatic cells, senescence serves as a potent barrier to malignant transformation[13]. Cellular senescence could be more significant than cell death for tumor suppression, because subtle perturbations in senescence regulatory network influence cancer susceptibility dramatically in mice whereas defects in apoptosis do not[13]. Cellular senescence induction has been suggested as a novel anti-cancer strategy

Methods

Results

Conclusion