MMSET is coordinately expressed with EZH2 and required for EZH2-dependent oncogenic phenotypes.

  • Major finding: MMSET is coordinately expressed with EZH2 and required for EZH2-dependent oncogenic phenotypes.

  • Mechanism: EZH2 relieves miRNA-mediated MMSET suppression and thus indirectly promotes H3K36 dimethylation.

  • Impact: EZH2 has broad functions in chromatin regulation that may be targetable by MMSET inhibition.

Overexpression of the histone methyltransferase enhancer of zeste 2 (EZH2) is observed in many solid tumor types and leads to epigenetic alterations that promote tumor growth, invasion, and metastasis. Small-molecule EZH2 inhibitors are therefore in clinical development, but recent studies have shown that direct targeting of EZH2 may be problematic because EZH2 may be a tumor suppressor in certain hematologic contexts. Asangani and colleagues hypothesized that, similar to a kinase cascade, other histone methyltransferases might function downstream of EZH2 and potentially represent targetable EZH2 surrogates. Analysis of gene and protein expression across multiple tumor types revealed that expression of multiple myeloma SET domain (MMSET) was strongly correlated with EZH2 and similarly associated with poor prognosis. Unlike EZH2, which is required for the repressive histone H3 lysine 27 (H3K27) trimethylation mark, MMSET catalyzes the H3K36 dimethylation mark associated with transcriptionally active chromatin. EZH2 knockdown led to a striking reduction in MMSET levels and global H3K36 dimethylation, indicating that MMSET functions downstream of EZH2. Indeed, MMSET was required for the increased invasion and intravasation that is characteristic of EZH2-overexpressing cells in culture and in chicken chorioallantoic membranes (CAM). Mechanistically, several microRNAs (miRNA) normally repressed by EZH2, miR-26a, miR-31, and miR-203, directly bound to the MMSET 3′-untranslated region and downregulated MMSET protein levels. EZH2 therefore indirectly promotes MMSET-mediated H3K36 dimethylation via miRNA regulation, which likely contributes to EZH2-mediated tumor formation and metastasis, as MMSET overexpression alone promoted tumor formation and metastasis in both CAM and murine xenograft models. Taken together, these data indicate that EZH2 plays a broader role in chromatin regulation than previously appreciated and suggest that MMSET inhibition may be an alternative therapeutic strategy to targeting EZH2.

Asangani IA, Ateeq B, Cao Q, Dodson L, Pandhi M, Kunju LP, et al. Characterization of the EZH2–MMSET histone methyltransferase regulatory axis in cancer. Mol Cell 2012 Nov 15 [Epub ahead of print].