Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

Abstract

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma

“…RNA sequencing. According to previously described RNA sequencing with minor modification 42 . Total RNA was extracted from BC cells using the RNeasy Mini Kit (Qiagen, German), and cDNA was synthesized using the SMART-Seq v4 Ultra Low Input RNA Kit for Sequencing (Clontech, Palo Alto, CA, USA).…”

Role of Polycomb Complexes in Normal and Malignant Plasma Cells

“…FOXO3 binds to the EZH1 promoter and stimulates its transcription. FOXO3 export from the nucleus by the PI3K/Akt pathway inhibits its transcriptional activity, explaining why Akt inhibition induces a compensatory EZH1 upregulation (at constant H3K27me3 levels) and EZH2 downregulation [101]. Therefore, as already demonstrated in acute myeloid leukemia [114], the concomitant inhibition of EZH1 and EZH2 appears to be an important element in MM and requires further study.…”

“…E2F1, which binds to the EZH2 promoter and induces its expression, is enriched in the nucleus of tumor PC due to the abnormally high basal activity of the PI3K/Akt pathway in MM. This explains why Akt inhibitors indirectly lower EZH2 level and have a synergistic effect with dual inhibitors that target both EZH2 and EZH1 [101]. Interestingly, this synergy is not observed with selective EZH2 inhibitors, suggesting a compensatory role for EZH1 in this context [101].…”

“…This explains why Akt inhibitors indirectly lower EZH2 level and have a synergistic effect with dual inhibitors that target both EZH2 and EZH1 [101]. Interestingly, this synergy is not observed with selective EZH2 inhibitors, suggesting a compensatory role for EZH1 in this context [101]. At the post-transcriptional level, loss of miR-26a, miR-101, let-7, and miR-138 increases EZH2 level in tumor PC [102][103][104].…”

Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies

“…Inhibitors targeting both EZH1 and EZH2 (EZH1/2 dual inhibitors) and EED (EED inhibitor) have also been developed [102][103][104], and these inhibitors show better tumoreradicating effects than EZH2-specific inhibitors in the treatment of AML, multiple myeloma, and EZH2 inhibitor-resistant DLBCL cells [105][106][107][108][109][110]. EED stabilizes and activates PRC2 to maintain H3K27 methylation for gene silencing.…”