Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment

Abstract

The anticancer therapies with the joint treatment of a histone deacetylase (HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A (TSA), could promote the degradation of the core histones induced by γ-radiation or the DNAalkylating agent methyl methanesulfonate (MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies. HDAC, histone deacetylase inhibitor, DNA damage, anticancer agent, histone degradation Citation:Yin, Y., Zhu, Q., Jiang, T., Fan, L., and Qiu, X. (2019). Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment. Sci

Histone degradation by the proteasome regulates chromatin and cellular plasticity

“…Therefore, in the case of prostate cancer, and potentially other cancer types, activation of SIRT1, rather than inhibition, will be beneficial as an anti‐cancer treatment. Such studies provide evidence for the therapeutic potential of compounds, which enhance HDAC activity (such as resveratrol) [ 111 ], in combination with other chromatin‐remodeling compounds that increase H2A.Z degradation by the proteasome, in cancer.…”

Silencing circular RNA hsa_circABCC1 inhibits osteosarcoma progression through down‐regulating HDAC4 via sponging miR‐591

“…Histones serve a key part in cancer development and are expected to be a novel strategy in cancer treatment 28 . It has been reported that histone deacetylase 4 (HDAC4) is highly expressed in osteosarcoma, 29 which can be involved in the development of osteosarcoma by regulating cellular behavior.…”

“…25,26 Our research data revealed that miR-591 was downregulated in OS, consistent with the results reported by Luo et al 27 It was also the first demonstration that overexpression of miR-591 could impede OS Histones serve a key part in cancer development and are expected to be a novel strategy in cancer treatment. 28 It has been reported that histone deacetylase 4 (HDAC4) is highly expressed in osteosarcoma, 29 which can be involved in the development of osteosarcoma by regulating cellular behavior. For example, HDAC4 inhibition by miR-140 inhibited OS proliferation, apoptosis and invasion, 17 while long noncoding RNA MALAT1 modulates HDAC4 through binding to miR-140-5p, thereby promoting HOS and 143B cell growth.…”