Knockdown of Rad9A enhanced DNA damage induced by trichostatin A in esophageal cancer cells

Abstract

Histone deacetylase (HDAC) inhibitors have recently emerged as a new class of anticancer agents. As a classical HDAC inhibitor, trichostatin A (TSA) has been shown to possess many anticancer activities such as induction of cell cycle arrest, promotion of cell death, and enhancement of radiosensitity. In our previous work, we found that TSA treatment induced Rad9 gene expression, which suggested that Rad9 might play a role in TSA-induced biological effects. As Rad9 is involved in maintaining genomic integrity, we further analyzed the DNA damage induced by TSA and combined with Rad9 knockdown in esophageal cancer cells (ESCCs). Our results showed that TSA treatment alone induced significantly DNA damage in ESCC cells. Simultaneously, TSA also induced Rad9 gene expression both at transcriptional and translational levels in EC109 cells, but not in KYSE150 cells. Further, the induction of Rad9 by TSA was accompanied with increased level of histone H3K9 acetylation in Rad9 promoter region. To understand the role of Rad9 in TSA-induced DNA damage, Rad9 gene expression was efficiently knocked down by small interfering RNA (siRNA), which led to enhanced DNA damage and cell death induced by TSA. Our data suggested that Rad9 plays an important role in DNA damage, which is related to the biological effects of TSA.

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

“…Treatment of cancer cells with broad-spectrum HDAC inhibitors such as vorinostat (suberoylanilide hydroxamic acid, SAHA) and trichostatin A (TSA) enhance DNA damage and impair non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) (Lee et al 2010; Pang et al 2016; Robert et al 2016; Vashishta and Hetman 2014). The exact role of single HDAC subtypes including HDAC8 and HDAC10 in DNA damage repair, however, is not yet fully understood.…”

“…Induction of DNA damage and inhibition of cellular DNA repair bear the potential to take advantage of malignant cells’ dysfunctional DNA damage response mechanisms and thus drive them into cell death while sparing non-malignant cells (Hosoya and Miyagawa 2014 ; Lord and Ashworth 2012 ). Treatment of cancer cells with broad-spectrum HDAC inhibitors such as vorinostat (suberoylanilide hydroxamic acid, SAHA) and trichostatin A (TSA) enhance DNA damage and impair non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) (Lee et al 2010 ; Pang et al 2016 ; Robert et al 2016 ; Vashishta and Hetman 2014 ). The exact role of single HDAC subtypes including HDAC8 and HDAC10 in DNA damage repair, however, is not yet fully understood.…”

The Seed Repair Response during Germination: Disclosing Correlations between DNA Repair, Antioxidant Response, and Chromatin Remodeling in Medicago truncatula

“…Duffy et al ( 2017 ) showed that human cells overexpressing the TDP1 gene were more sensitive to TSA whereas Meisenberg et al ( 2017 ) suggested that TSA influences the repair of DSBs resulting from topo I/DNA cleavage complexes through a TDP1/TDP2-independent mechanism. The study by Pang et al ( 2016 ) showed that TSA induces DSBs in human cancer cells, triggering at the same time the RAD9 ( RADIATION SENSITIVE ) gene expression through promoter hyperacetylation. RAD9 is part of the 9-1-1 complex, early sensor of genotoxic stress, able to control G 1 /S transition.…”

MiR-2425-5p targets RAD9A and MYOG to regulate the proliferation and differentiation of bovine skeletal muscle-derived satellite cells

“…As a component of RAD9A-HUS1-RAD1 (9-1-1) complex, RAD9A promotes genomic repair when DNA is damaged 33 . As such, abnormal expression of RAD9A has been linked to tumorigenesis 34 . In comparison, MYOG is an important myogenic regulatory factor necessary for myocyte differentiation and the development of functional skeletal muscle 35 .…”