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

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.

The Cancer SENESCopedia: A delineation of cancer cell senescence

“…Three incorrectly classified samples were from Wang et al (2019): SK-Hep1 cells treated with XL413, which were described as non-senescent due to their wild-type TP53 status but scored as senescent by the classifier (score of 0.81); and PLC and Hep3B cells treated with XL413, which were defined as senescent, but received a non-senescent score (0.10 and 0.37, respectively). The H2A.Z knockdown samples from Á vila-Ló pez et al (2021) were also not classified as senescent, but it should be noted that although these samples were described as senescent, they contained fewer than 50% of senescent cells (Á vila-Ló pez et al, 2021). This indicates that the classifier may only classify a sample as senescent if the majority of cells are senescent.…”

E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

“…Notably, two distinct isoforms of H2AZ variant histone, namely H2AZ1 and H2AZ2 that are encoded by two non-allelic genes and differ only by three amino acids, are overexpressed in multiple cancers [ 12 – 15 ]. Like their canonical counterparts, the main function of variant histone proteins is to generate nucleosomes for genome organization within the nucleus.…”

MALDI Mass Spectrometry Imaging for the Distinction of Adenocarcinomas of the Pancreas and Biliary Tree

“…For these proteins, there are already multiple studies in connection with PDAC to be found in the literature. H2A.Z isoforms were reported to be overexpressed in PDAC cell lines and PDAC tissues, resulting in tumor growth and resistance to chemotherapy [ 23 ]. In this study, Avila-Lopez et al demonstrated that the depletion of H2A.Z isoforms promotes tumor senescence, increases sensitivity to the chemotherapeutic drug gemcitabine, and decreases tumor growth in a mouse xenograft model in vivo.…”