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J Mol Cell Biol. 2018 Apr 1;10(2):147-160. doi: 10.1093/jmcb/mjy007.

PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4.

Long W1,2, Zhao W2,3, Ning B2,4, Huang J2, Chu J3, Li L2, Ma Q1,2, Xing C2, Wang HY2, Liu Q1, Wang RF2,5,6.

Author information

1
Department of Neurosurgery in Xiangya Hospital, Central South University, Changsha 410008, China.
2
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
3
Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
4
Institute Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
5
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
6
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.

Abstract

The differentiation status of neuroblastoma (NB) strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of stemness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 (PHF20) functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Cas9-based targeted knockout (KO) for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem cell-like traits. Mechanistically, PHF20 interacts with poly(ADP-ribose) polymerase 1 (PARP1) and directly binds to promoter regions of octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2) to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit (H3K4me3). Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.

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