MMSET is highly expressed and associated with aggressiveness in neuroblastoma.
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MMSET is highly expressed and associated with aggressiveness in neuroblastoma. / Hudlebusch, Heidi Rye; Skotte, Julie; Santoni-Rugiu, Eric; Zimling, Zarah Glad; Lees, Michael James; Simon, Ronald; Sauter, Guido; Rota, Rossella; Ioris, De; Antonietta, Maria; Quarto, Micaela; Johansen, Jens Vilstrup; Jørgensen, Mette; Rechnitzer, Catherine; Maroun, Lisa Leth; Schrøder, Henrik; Petersen, Bodil Laub; Helin, Kristian.
in: CANCER RES, Jahrgang 71, Nr. 12, 12, 2011, S. 4226-4235.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - MMSET is highly expressed and associated with aggressiveness in neuroblastoma.
AU - Hudlebusch, Heidi Rye
AU - Skotte, Julie
AU - Santoni-Rugiu, Eric
AU - Zimling, Zarah Glad
AU - Lees, Michael James
AU - Simon, Ronald
AU - Sauter, Guido
AU - Rota, Rossella
AU - Ioris, De
AU - Antonietta, Maria
AU - Quarto, Micaela
AU - Johansen, Jens Vilstrup
AU - Jørgensen, Mette
AU - Rechnitzer, Catherine
AU - Maroun, Lisa Leth
AU - Schrøder, Henrik
AU - Petersen, Bodil Laub
AU - Helin, Kristian
PY - 2011
Y1 - 2011
N2 - 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 = 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 acid-induced 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.
AB - 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 = 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 acid-induced 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.
KW - Humans
KW - Prognosis
KW - Cell Proliferation
KW - Cell Differentiation
KW - Genes, myc
KW - Repressor Proteins/analysis/physiology
KW - Histone-Lysine N-Methyltransferase/analysis/physiology
KW - Neural Stem Cells/chemistry/cytology
KW - Neuroblastoma/drug therapy/etiology/pathology
KW - Humans
KW - Prognosis
KW - Cell Proliferation
KW - Cell Differentiation
KW - Genes, myc
KW - Repressor Proteins/analysis/physiology
KW - Histone-Lysine N-Methyltransferase/analysis/physiology
KW - Neural Stem Cells/chemistry/cytology
KW - Neuroblastoma/drug therapy/etiology/pathology
M3 - SCORING: Journal article
VL - 71
SP - 4226
EP - 4235
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 12
M1 - 12
ER -
