Chromatin-regulating proteins as targets for cancer therapy

Abstract

Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow's cancer therapy, including radiotherapy and molecularly targeted chemotherapy.

Keywords: BRM; SWI/SNF complex; chromatin remodeling; histone acetyltransferase; histone modification; synthetic lethality.

Fig. 1.

Chromatin structure and its alteration by two distinct mechanisms: histone modification and chromatin remodeling. (a) Structure of chromatin and nucleosome. (b) Examples of histone modification. Ac = acetylation, PAR = poly-ADP-ribosylation, P = phosphorylation, SUMO = SUMOylation, Ub = ubiquitination. (c) Chromatin remodeling: DNA-loop formation (left) and nucleosome sliding (right).

Fig. 2.

Composition of the SWI/SNF chromatin remodeling complex.

Fig. 3.

Specific cell killing of BRG1-deficient H1299 cells, but not BRG-proficient HeLa cells, by BRM knockdown based on synthetic lethality. Cells were treated with BRM-siRNA (BRM knockdown) or non-targeting siRNA (control) (Dharmacon). After 48 h, the cells were subjected to clonogenic survival assays. Colonies fixed and stained after incubation for an additional 10 d are shown.