Chromatin Stability as a Target for Cancer Treatment

Abstract

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. DNA in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization.

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

“…Ongoing studies of chromatin assembly in cancer cells are aimed at dissecting the dysregulated replication stress-related pathways and instability hotspots and may give rise to new epigenetic therapy strategies. [77][78][79][80]…”

Cura“x”ing Cancer and Beyond

“…A widely employed approach to eliminate cancer cells is to disrupt their genome by using agents that either induce DNA damage or affect chromatin assembly. Typical genotoxic compounds include cisplatin and doxorubicin, while hypomethylating factors such as azacitidine or HDAC inhibitors are representative chromatin‐modifying agents …”

“…However, other compounds act at the “interface” between DNA and chromatin organization. In the current issue of BioEssays, Katerina Gurova provides an interesting perspective on new small molecules – named curaxins – that bind DNA, but do not induce DNA damage as do typical chemotherapeutic agents . Instead these compounds interfere with the assembly of nucleosomes along the DNA, and thus destabilize chromatin.…”

“…The unremitting occurrence of DNA damage, from processes like replication stress and/or erroneous repair, requires constant histone remodeling to accommodate the evolving genome plasticity of malignant cells. Moreover, as K Gurova suggests, this chromatin destabilization in malignant cells also promotes aberrant transcription, causing further chromatin relaxation . Consequently, curaxins interfere more frequently with histones/nucleosome assembly in malignant cells than normal ones, which do not experience such events.…”

“…At a mechanistic level, curaxins inhibit the histone chaperone FACT that stabilizes chromatin through preventing histone loss . Down‐regulation of FACT and loss of histones are features of a phenomenon termed cellular senescence [ref.…”