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Cell Stem Cell. 2019 Apr 4;24(4):637-653.e9. doi: 10.1016/j.stem.2019.03.011.

Yin Yang 1 Orchestrates a Metabolic Program Required for Both Neural Crest Development and Melanoma Formation.

Author information

1
Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland.
2
VIB Center for Brain & Disease Research, Laboratory of Computational Biology, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
3
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
4
Department of Dermatology, University of Zurich Hospital, 8091 Zurich, Switzerland.
5
Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
6
Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland. Electronic address: lukas.sommer@anatomy.uzh.ch.

Abstract

Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program.

KEYWORDS:

YY1; development; melanoma; metabolism; neural crest; protein synthesis; tumor initiation

PMID:
30951662
DOI:
10.1016/j.stem.2019.03.011

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