Untangling the Role of Polycomb Complexes in Chemotherapy Resistance

Abstract

In this issue, Maganti and colleagues described an epigenetic link between reduced abundance of Polycomb-related protein MTF2 and chemotherapy resistance in refractory acute myeloid leukemia. MTF2 deficiency impaired expression of the PRC2 complex and deposition of H3K27me3 at many genes, including the key target gene MDM2, leading to increased MDM2 expression that in turn depleted p53 and thereby conferred chemoresistance. Cancer Discov; 8(11); 1348-51. ©2018 AACR See related article by Maganti et al., p. 1376.

Figure 1.

Epigenetic regulation of MTF2–PRC2 involved in chemoresistance in AML. A, The MTF2 promoter is hypermethylated (red) in MTF2-deficient AMLs that are significantly more unresponsive/resistant to induction therapy without undergoing complete remission (defined as refractory AML). In contrast, chemosensitive AML contains unmethylated CpG islands at the MTF2 promoter and expresses basal (normal) MTF2 mRNA levels. B, MTF2 mediates silencing of MDM2 in chemosensitive AML, whereas refractory, MTF2-deficient AMLs exhibit abundant levels of MDM2. MTF2 knockdown results in posttranslational reduction of the PRC2 core proteins EZH1, EZH2, and SUZ12 with concomitant reduction of H3K27me3, linked to increased chemoresistance (blue arrow). Conversely, rescue of MTF2 through ectopic expression in MTF2-deficient leukemia cells restores H3K27me3 levels that are associated with reduced chemoresistance. C, PRC2-mediated silencing of the MDM2 locus renders leukemia cells sensitive to chemotherapy (cytarabine and daunorubicin) through activation of the p53 pathway in response to DNA damage. On the other hand, refractory AML cells resist chemotherapy-induced DNA damage through MDM2-mediated depletion of p53. Inhibition of MDM2 (Nutlin-3a or MI-773) renders refractory cells sensitive to chemotherapy. D, Top plot shows that inhibition of EZH2 with specific SAM-competitive inhibitors (EPZ005687, GSK126) confers non-to minimal increase in drug tolerance (for cytarabine and daunorubicin) in contrast to dual inhibition of EZH1 and EZH2 (UNC1999). Inhibition with the SAH inhibitor DZNep (used as an EZH2 inhibitor) also affects other PRC core components leading to depletion/degradation of the whole PRC complex. DZNep treatment increases drug tolerance in AML. Bottom plot shows that knockdown of EED, SUZ12, or EZH2 induced drug tolerance, presumably through perturbation that can affect scaffolding or stoichiometry of the PRC2 complex. This can either cause depletion/degradation of the complex or potentially induce divergent functions by compensating proteins (e.g., EZH2 vs. EZH1). AML carrying frameshift mutations in EZH2 possibly perturb the stoichiometry of the PRC2 complex as well. The role of EZH2 missense mutations is unknown in AML.