H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma

P A Ávila-López,C A Peralta-Alvarez,G Guerrero,J Albores-Saavedra,G Hernández-Montes,L Cedillo-Barrón,M Schnoor,F Recillas-Targa,N Villegas-Sepúlveda,L G Álvarez-Hilario,R Hernández-Rivas,R Herrera-Goepfert,A E Montes-Gómez,H N Nuñez-Martínez,M Vargas

doi:10.1038/s41388-021-01664-1

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-β-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is characterized by altered DNA methylation, histone post-translational modifications (PTMs) and expression of microRNAs that all contribute to its development and progression [25]
We found that H2A.Z was upregulated significantly in three different PDAC cell lines (Capan-1, MiaPaCa-2, and PANC-1) compared to the normal ductal pancreatic cell line hTERT-HPNE (Fig. 1a)
Using cytokeratin 7 (CK7) as a specific marker of ductal pancreatic cells, we could demonstrate that H2A.Z overexpression occurred in these cells in 51 PDAC samples compared to 22 normal pancreas samples (Table 1) (Fig. 1b and Supplementary Fig. 1a)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal cancers in the world, primarily due to its late diagnosis and resistance to gemcitabine, the first-line chemotherapy [1, 2]. Genetic alterations in PDAC have been widely studied [3, 5]. Epigenetic mechanisms might contribute to regulating gene expression [5, 6]. Molecular mechanisms underlying epigenetic effects have been attributed primarily to alterations in DNA methylation patterns, and histones have emerged as critical regulators [7]. Histones can alter the epigenomic landscape mainly by two mechanisms: (1) histone post-translational modifications (PTMs) such as methylation, acetylation, ubiquitination, and phosphorylation; and (2) the substitution

Methods

Results

Conclusion