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

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.

<p>Repression of PCGF1 Decreases the Proliferation of Glioblastoma Cells in Association with Inactivation of c-Myc Signaling Pathway</p>

“…23,24 Recent research has indicated that polycomb group members, such as EZH2, Bmi1, KDM2B, PHF19, SUZ12, CBX8, and so on, are involved in the proliferation of cancer cell including glioma cells. 20,[25][26][27][28][29][30][31] In the present study, we revealed the association between PCGF1 and various characteristics of glioblastoma (GBM).…”

hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells

“…Recent follow-up studies have finely deciphered the mechanisms implicating hPL3L/PHF9L and hPCL3S in several cancer types including glioblastomas [45], hepatocellular carcinomas [25], multiple myelomas [46], and prostate (this study). Despite the low number of studies, a clear-cut situation seems to emerge with two different mechanisms for hPCL3L/PHF19 and hPCL3S.…”

“…Indeed, in close agreement with its function as a PRC2 facultative subunit [10,14], PHF19/hPCL3L amplification is correlated with the activation of PRC2 and thus increased H3K27me deposition whereas hPCL3S is clearly involved in PRC2-independent mechanisms. In gliomas, Deng et al, reported that PHF19 is up-regulated and promotes the proliferation and migration of glioblastoma cell lines through direct repression of the promoter of SIAH (seven in absentia homolog 1), an E3-ubiquitin ligase of β-catenin and thus activation of the Wnt/βcatenin pathway [45]. However, the potential contribution of hPCL3S/PHF19S which is known to be expressed concomitantly with hPCL3L in several glioblastomas cell lines [21] has not been carefully investigated [45].…”

“…In gliomas, Deng et al, reported that PHF19 is up-regulated and promotes the proliferation and migration of glioblastoma cell lines through direct repression of the promoter of SIAH (seven in absentia homolog 1), an E3-ubiquitin ligase of β-catenin and thus activation of the Wnt/βcatenin pathway [45]. However, the potential contribution of hPCL3S/PHF19S which is known to be expressed concomitantly with hPCL3L in several glioblastomas cell lines [21] has not been carefully investigated [45]. In a recent study, PHF19L has been clearly identified as a crucial mediator of oncogenesis in multiple myeloma through activation of PRC2 [46].…”

PHD Finger Protein 19 Enhances the Resistance of Ovarian Cancer Cells to Compound Fuling Granule by Protecting Cell Growth, Invasion, Migration, and Stemness

“…Generally, recruitment of PRC2 to DNA regions of target genes to catalyze the methylation of lysine 27 on histone 3 (H3K27me3), are essential for controlling the developmental gene expression and maintaining cell specification (Kouznetsova et al, 2019). Aberrant expression of PHF19 has been implicated in regulating the pathogenesis and progression of a wide range of cancers, including melanoma (Ghislin et al, 2012), hepatocellular carcinoma (Xu et al, 2015;Cai et al, 2018), glioma (Lu et al, 2018), glioblastoma (Deng et al, 2018), multiple myeloma (Ren et al, 2019). In our previous publication, we have found that patients with higher expression of PHF19 are associated with shorter progressionfree survival (PFS) than that with lower PHF19 expression.…”