PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β-catenin axis

Qing Deng; Jianbing Hou; Liying Feng; Ailing Lv; Xiaoxue Ke; Hanghua Liang; Feng Wang; Kui Zhang; Kuijun Chen; Hongjuan Cui

doi:10.1038/s41419-018-1082-z

PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β-catenin axis

Cell Death Dis. 2018 Oct 15;9(11):1049. doi: 10.1038/s41419-018-1082-z.

Authors

Affiliations

¹ State Key Laboratory of Silkworm Genome Biology, The Institute of Sericulture and Systems Biology, Southwest University, 400716, Chongqing, People's Republic of China.
² Department 6 of the Research Institute of Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, 400042, Chongqing, People's Republic of China.
³ State Key Laboratory of Silkworm Genome Biology, The Institute of Sericulture and Systems Biology, Southwest University, 400716, Chongqing, People's Republic of China. [email protected].

Abstract

PHD finger protein 19 (PHF19), a critical component of the polycomb repressive complex 2 (PRC2), is crucial for maintaining the repressive transcriptional activity of several developmental regulatory genes and plays essential roles in various biological processes. Abnormal expression of PHF19 causes dysplasia or serious diseases, including chronic myeloid disorders and tumors. However, the biological functions and molecular mechanisms of PHF19 in glioblastoma (GBM) remain unclear. Here, we demonstrated that PHF19 expression was positively associated with GBM progression, including cell proliferation, migration, invasion, chemosensitivity, and tumorigenesis. Using XAV-939, a Wnt/β-catenin inhibitor, we found that the effects of PHF19 on GBM cells were β-catenin-dependent. We also demonstrated that PHF19 expression was positively correlated with cytoplasmic β-catenin expression. PHF19 stabilized β-catenin by inhibiting the transcription of seven in absentia homolog 1 (SIAH1), an E3 ubiquitin ligase of β-catenin, through direct binding to the SIAH1 promoter region. Taken together, our results revealed the novel PHF19-SIAH1-β-catenin axis as a potential and promising therapeutic target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects
Apoptosis / genetics
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics*
Brain Neoplasms / mortality
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Doxorubicin / pharmacology*
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic*
Glioblastoma / drug therapy
Glioblastoma / genetics*
Glioblastoma / mortality
Glioblastoma / pathology
Heterocyclic Compounds, 3-Ring / pharmacology
Humans
Male
Mice
Mice, Nude
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Survival Analysis
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism
Ubiquitin-Protein Ligases / genetics*
Ubiquitin-Protein Ligases / metabolism
Xenograft Model Antitumor Assays
beta Catenin / antagonists & inhibitors
beta Catenin / genetics*
beta Catenin / metabolism

Substances

Antibiotics, Antineoplastic
CTNNB1 protein, human
DNA-Binding Proteins
Heterocyclic Compounds, 3-Ring
Nuclear Proteins
PHF19 protein, human
RNA, Small Interfering
Transcription Factors
XAV939
beta Catenin
Doxorubicin
Ubiquitin-Protein Ligases
seven in absentia proteins