Universität zu Köln

Fabian, Johannes, Lodrini, Marco, Oehme, Ina, Schier, Marie C., Thole, Theresa M., Hielscher, Thomas, Kopp-Schneider, Annette ORCID: 0000-0002-1810-0267, Opitz, Lennart, Capper, David ORCID: 0000-0003-1945-497X, von Deimling, Andreas ORCID: 0000-0002-5863-540X, Wiegand, Inga, Milde, Till ORCID: 0000-0002-7267-1052, Mahlknecht, Ulrich, Westermann, Frank, Popanda, Odilia, Roels, Frederik, Hero, Barbara, Berthold, Frank, Fischer, Matthias, Kulozik, Andreas E., Witt, Olaf and Deubzer, Hedwig E. (2014). GRHL1 Acts as Tumor Suppressor in Neuroblastoma and Is Negatively Regulated by MYCN and HDAC3. Cancer Res., 74 (9). S. 2604 - 2617. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here, we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. Grainyhead-like 1 (GRHL1), a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genomewide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN colocalized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation, and retarded xenograft growth in mice. GRHL1 knockdown in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading, and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma. (C) 2014 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fabian, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Lodrini, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Oehme, Ina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schier, Marie C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thole, Theresa M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hielscher, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopp-Schneider, Annette UNSPECIFIED orcid.org/0000-0002-1810-0267 UNSPECIFIED Opitz, Lennart UNSPECIFIED UNSPECIFIED UNSPECIFIED Capper, David UNSPECIFIED orcid.org/0000-0003-1945-497X UNSPECIFIED von Deimling, Andreas UNSPECIFIED orcid.org/0000-0002-5863-540X UNSPECIFIED Wiegand, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Milde, Till UNSPECIFIED orcid.org/0000-0002-7267-1052 UNSPECIFIED Mahlknecht, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Popanda, Odilia UNSPECIFIED UNSPECIFIED UNSPECIFIED Roels, Frederik UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Kulozik, Andreas E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Witt, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Deubzer, Hedwig E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-439896
DOI:	10.1158/0008-5472.CAN-13-1904
Journal or Publication Title:	Cancer Res.
Volume:	74
Number:	9
Page Range:	S. 2604 - 2617
Date:	2014
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-RISK NEUROBLASTOMA; PEDIATRIC SOLID TUMORS; B-CELL LYMPHOMAS; HISTONE DEACETYLASE; GENE-EXPRESSION; N-MYC; INHIBITOR; CLASSIFICATION; TRANSCRIPTION; RECRUITMENT Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43989