PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia

Abstract

Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that was overexpressed in primary CML CD34 cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism. Human primary CML CD34 cells and retrovirally -driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by- or -specific shRNA and Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene in CML cells was measured by chromatin immunoprecipitation assay. Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34 cells while sparing those from normal bone marrow CD34 cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. knockdown resulted in elevation of and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of gene. The effect of knockdown in the CML mice was at least partially reversed by knockdown. These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. .

Salinomycin effectively eliminates cancer stem-like cells and obviates hepatic metastasis in uveal melanoma

“…Cytosolic fraction for cytochrome c detection was prepared using the digitonin extraction buffer (10 mmol/L PIPES, 0.015% digitonin, 300 mmol/L sucrose, 100 mmol/L NaCl, 3 mmol/L MgCl 2 , 5 mmol/L EDTA, and 1 mmo/L phenylmethylsulfonyl fluroride) [30]. Briefly, cell pellets were suspended in digitonin extraction buffer on ice for 10 min.…”

Gene amplification derived a cancer‐testis long noncoding RNA PCAT6 regulates cell proliferation and migration in hepatocellular carcinoma

“…To further evaluate the oncogenic role of PCAT6, we performed a correlation analysis to explore the relationship between PCAT6 and stemness. However, we found that the expression of PCAT6 showed a significantly negative association with CD34 , a marker of stemness (Figure A) (r = −0.12, P = 1.97 × 10 −2 ) . Additionally, no relationship was observed between PCAT6 and mRNAsi (mRNA expression‐based stemness index)/mDNAsi (DNA methylation‐based stemness index) (r = −0.07, P = 1.76 × 10 −1 ; r = 0.03, P = 5.71 × 10 −1 ; Figure B).…”

PCAT‐1 contributes to cisplatin resistance in gastric cancer through epigenetically silencing PTEN via recruiting EZH2

“…PCAT‐1 has been reported to silence gene expression by recruiting EZH2, a vital catalytic subunit of polycomb repressive complex 2 complex (PRC2), to the specific genome sites of target genes . Moreover, PTEN could be suppressed by EZH2 through the enrichment of H3K27me3 on its promoter region in various cancers . Thus, we wondered whether PCAT‐1 epigenetically repressed PTEN through EZH2 in GC.…”