Cancer cells evolve throughout disease progression and tumor relapse. Such evolution is a dynamic process resulting in genotypic and phenotypic cellular changes, conferring a high level of cell plasticity. Data derived from next-generation sequencing strategies have implicated that cancer cell plasticity could be driven by genetic changes induced by genomic instability during cancer evolution. Understanding the mechanisms of how genomic instability promotes mutagenesis and cancer cell plasticity could thus be critical avenue for cancer prevention and intervention. In this review, we discuss the relationships between cancer cell plasticity, genomic instability and mutagenesis during cancer evolution. We offer our insight and opinion on therapeutic strategies in this rapidly progressing research field.
Dysregulation of redox homeostasis and the resulting generation of excessive reactive oxygen species (ROS) and oxidative DNA damage play an obligatory role in the progression of human cancer as well as therapeutic sensitivity to a variety of genome-targeting cancer drugs. In a recent study, Bao et al. (Free Radic Biol Med, 2020), present a novel mechanism that governs the sensitivity of certain cancer cells to DNA damaging therapies. The authors have identified a novel, ROS-associated, lysine acetylation modification in Uracil-DNA N-glycosylase 2 (UNG2)—a key understudied component of the base excision repair pathway, which primes UNG2 for subsequent ubiquitination by UHRF1 ligase, leading to coupling the UNG2 degradation to cancer cell death in a ROS-sensitive manner. Translational innovation of these mechanistic findings resides by the ability of epigenetic therapeutic inhibitors to elevate the levels of UNG2-Lys78 acetylation, leading to sensitizing ROS-resistant cancer cells to DNA damaging therapeutic agents. I close this commentary by briefly summarizing some outstanding questions and postulations in the field in the context of the novel findings presented by Bao et al.
DNA damage can be caused by both endogenous and environmental factors, such as replication errors, reactive oxygen species (ROS) and chemotherapeutic drugs. Accurate and effective repair of DNA damage can preserve the integrity of the genome. However, if left unrepaired or repaired inappropriately, DNA damage could lead to the development of a variety of diseases, including cancers. DNA damage response (DDR) pathways are regarded as attractive tumor therapeutic targets. In recent years, representative drugs like poly(ADP-ribose) (PAR) polymerase inhibitors (PARPis) target DNA damage repair pathways and thus have generated profound breakthroughs in the treatment of tumors. Therefore, it is necessary to understand the mechanisms behind these drugs for treating tumors. In this review, we will discuss the mechanisms of representative tumor therapeutic drugs in the field of DNA damage repair and our current understanding of the related inhibitors that are expected to be used in future cancer therapies. We believe that these underlying mechanisms will provide significant support for directing drug use and future drug development.
Tat interacting protein 60 (TIP60) is a histone acetyltransferase involved in chromatin remodeling and the DNA damage response. However, the role of TIP60 in maintaining genome stability is poorly understood. Here, we show that TIP60 can directly interact with suppressor of variegation 3–9 homologue 1 (SUV39H1), a methyltransferase that is responsible for histone H3 tri-methylation on Lys9 (H3K9me3). When we knocked down TIP60 or treated cells with hydrogen peroxide, a typical reactive oxygen species (ROS) generator that induces genome instability, SUV39H1 dissociated from chromatin but its acetylation levels remained unchanged. Consequently, H3K9me3 levels in the heterochromatin decreased, leading to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Micrococcal nuclease sensitivity and colony formation assays further demonstrated that TIP60 knockdown or hydrogen peroxide treatment resulted in a relaxing of the heterochromatin and genome instability. Exogenous TIP60 could rescue the assembly of SUV39H1 on chromatin and ensure genome stability in response to hydrogen peroxide. This study is the first to describe a role for TIP60 in maintaining heterochromatin structure and genome stability by recruiting SUV39H1 to the chromatin upon oxidative stress, presenting TIP60 as a promising target to sensitize cancer cells to ROS-promoting therapies.