MMSET Is Highly Expressed and Associated with Aggressiveness in Neuroblastoma

Abstract

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n ¼ 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre-and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acidinduced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis. Cancer Res; 71(12); 4226-35. Ó2011 AACR.

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

“…Indeed, NSD2 is overexpressed in neuroblastoma, lung, colon and bladder cancer [61,62], and is required for proliferation of neuroblastoma cells and brain-derived neural stem cells [62]. An E1099K mutation in the SET domain of 1594 Future Med.…”

“…Indeed, NSD2 is overexpressed in neuroblastoma, lung, colon and bladder cancer [61,62], and is required for proliferation of neuroblastoma cells and brain-derived neural stem cells [62]. An E1099K mutation in the SET domain of future science group Review Rogawski, Grembecka & Cierpicki NSD2 was identified in a range of human cancer cell lines and tumor samples, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lung cancer and stomach cancer [63,64].…”

Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress

“…First, WHSC1 transcripts are consistently overexpressed in t(4;14)-positive myelomas, and WHSC1 is also upregulated by unknown mechanisms in subsets of diverse solid tumor types, including neuroblastoma, in which high WHSC1 levels are associated with tumor aggressiveness (14)(15)(16). Second, transcriptional deregulation by the HMT encoded by WHSC1 is a plausible mechanism of carcinogenesis.…”

“…Indeed, H3K36 methyltransferase activity can be sufficient to initiate malignant transformation (17), and attractive candidate target genes and pathways have been identified for WHSC1 (18,19). Third, WHSC1 knockdown using shRNAs decreases cell growth and cell adhesion in MM and neuroblastoma cell lines (8,10,15,20). Knockdown using a variety of shRNA constructs has established the dependence of transformed cells on WHSC1 expression, but which WHSC1 isoform is responsible for cell transformation has not been clearly established.…”

Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

“…Deletion of the gene encoding the histone H3K36 dimethyltransferase enzyme nuclear receptor binding SET domain protein 2 (NSD2) (also known as WHSC1 or MMSET), specifically, is present in the developmental disorder Wolf-Hirschhorn syndrome (9). By contrast, NSD2 overexpression, as a result of a t(4;14) chromosomal translocation (10), is manifest in 15% of multiple myeloma cases and has been identified in other cancers (11)(12)(13). NSD2 catalyzes the monomethylation and dimethylation of histone H3K36 in vivo (11), although other CH 3 -transfer specificities have also been reported in studies using histone protein or histone tail peptide as substrate analogs (14)(15)(16).…”