3‐Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor‐initiating hepatocellular carcinoma cells

Abstract

Recent advances in stem cell biology have identified tumor-initiating cells (TICs) in a variety of cancers including hepatocellular carcinoma (HCC). Polycomb group gene products such as BMI1 and EZH2 have been characterized as general self-renewal regulators in a wide range of normal stem cells and TICs. We previously reported that Ezh2 tightly regulates the self-renewal and differentiation of murine hepatic stem/progenitor cells. However, the role of EZH2 in tumor-initiating HCC cells remains unclear. In this study, we conducted loss-of-function assay of EZH2 using short-hairpin RNA and pharmacological inhibition of EZH2 by an S-adenosylhomocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep). Both EZH2-knockdown and DZNep treatment impaired cell growth and anchorage-independent sphere formation of HCC cells in culture. Flow cytometric analyses revealed that the two approaches decreased the number of epithelial cell adhesion molecule The minor population, termed CSCs or tumor-initiating cells (TICs), organize a cellular hierarchy in a similar fashion to normal stem cell systems and exhibit pronounced tumorigenic activity in xenograft transplantation. 3,4 Recent progress in stem cell biology and technologies has facilitated the identification of TICs in a variety of cancers. 5 We previously applied side population (SP) analysis and cell sorting to

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

“…We reported previously that DZNep, but not 5-fluorouracil, reduced the number of tumor-initiating cells significantly in a mouse model of hepatocellular carcinoma. 20 Together with AML's higher requirement for EZH2, it could be a potential target for epigenetic therapy aimed at the leukemic stem cells in AML.…”

“…DNZep, an S-adenosylhomocysteine hydrolase inhibitor, has been shown to eradicate tumor-initiating hepatocellular carcinoma cells and to induce apoptosis preferentially in cancer cells in other cancers, including AML. [20][21][22] DZNep inhibits S-adenosylhomocysteine hydrolase and causes the retention of S-adenosylhomocysteine, thereby inhibiting S-adenosyl-L-methionine-dependent methyltransferases such as EZH2. 23 However, DZNep is not a specific inhibitor of EZH2, so it affects other S-adenosyl-L-methionine-dependent methyltransferases For personal use only.…”

Epigenetic regulation of hepatic tumor-initiating cells

“…For instance, as a selfrenewal regulator, EZH2, modulates the self-renewal and © 1996-2015 differentiation of hepatic stem cells. 3-Deazaneplanocin A (DZNep), an EZH2 pharmacological inhibitor, decreased EpCAM + T-IC subpopulation and suppressed tumorigenesis in NOD-SCID mice (117). In this context, the use of EZH2 inhibitors, such as an S-adenosylhomocysteine hydrolase inhibitor, DZNep, might be a promising strategy through targeting hepatic T-ICs (117).…”

“…3-Deazaneplanocin A (DZNep), an EZH2 pharmacological inhibitor, decreased EpCAM + T-IC subpopulation and suppressed tumorigenesis in NOD-SCID mice (117). In this context, the use of EZH2 inhibitors, such as an S-adenosylhomocysteine hydrolase inhibitor, DZNep, might be a promising strategy through targeting hepatic T-ICs (117). A demethylating agent, zebularine, increased self-renewal and tumorigenicity of low density HCC cells.…”

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

“…Report revealed that the use of agent disrupting PRC2 subunits is a relevant way to affect PRC2 function (Tan et al, 2007). Although currently there is no EZH2 specific inhibitor, but agent such as DZnep is also able to deplete the cellular EZH2, inhibit EZH2 functions and lower the H3K27 trimethylation level (Chiba et al, 2011). This fundamental knowledge surely enables researchers to design potent agents to target EZH2 in HCC.…”