PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation

Ren, Zhihong; Ahn, Jeong Hyun; Liu, He-Qun; Tsai, Yi-Hsuan; Bhanu, Natarajan V.; Koss, Brian; Allison, David F.; Ma, Anqi; Storey, Aaron J.; Wang, Ping; Mackintosh, Samuel G.; Edmondson, Ricky D.; Groen, Richard W.J.; Martens, Anton C.; García, Benjamin A.; Tackett, Alan J.; Jin, Jian; Cai, Ling; Zheng, Deyou; Wang, Gang Greg

doi:10.1182/blood.2019000578

Cited by 60 publications

(83 citation statements)

References 79 publications

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“…shRNA induced cells showed knockdown (KD) of >90% PHF19 RNA and protein relative to the control after 72 hrs and 168 hrs for the JJN3 and ARP1 cell lines, respectively (Figure 4a and 4b). KD of PHF19 led to significant inhibition of proliferation in the JJN3 and ARP1 MM cell lines compared to scrambled shRNA control (Figure 4c-d) confirming the recent finding of PHF19's effect on proliferation in MM cell lines 27 . To identify the mechanism of growth inhibition, we performed cell cycle analysis and observed a significant arrest of MM cells in the G0/G1 stage with PHF19 KD compared to the scrambled control shRNA (Supplemental Figure 3a).…”

Section: Knockdown Of Phf19 Leads To Decreased Proliferation Throughsupporting

confidence: 86%

Multiple Myeloma DREAM Challenge Reveals Epigenetic RegulatorPHF19As Marker of Aggressive Disease

Mason

Schinke

Eng

et al. 2019

Preprint

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Key points• Most comprehensive and unbiased assessment of prognostic biomarkers in MM resulting in a robust and parsimonious model. •Identification of PHF19 as the expression based biomarker most strongly associated with rapid progression in MM patients. AbstractWhile the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients do not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involve assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post challenge analysis identified a novel expression-based risk marker and histone modifier, PHF19, which featured prominently in several independent models. Lastly, we show that a simple four feature predictor composed of age, International Staging System stage (ISS), and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.

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Section: Knockdown Of Phf19 Leads To Decreased Proliferation Throughsupporting

confidence: 86%

Multiple Myeloma DREAM Challenge Reveals Epigenetic RegulatorPHF19As Marker of Aggressive Disease

Mason

Schinke

Eng

et al. 2019

Preprint

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“…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.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2020

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Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/ PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the fulllength hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2, and Spondin1. Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, this increase in expression correlated with cancer progression (Wang et al, 2004). After that, accumulating evidence uncover the oncogenic role of PHF19 in a wide range of tumors (Ghislin et al, 2012;Xu et al, 2015;Lu et al, 2018;Tao et al, 2018b;Ren et al, 2019). For instance, PHF19 knockdown reduces the cell proliferation rate and increases the migration capacities of melanoma cells (Ghislin et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

“…For instance, PHF19 knockdown reduces the cell proliferation rate and increases the migration capacities of melanoma cells (Ghislin et al, 2012). In myeloma, PHF19 promotes its tumorigenesis through activating PRC2 complex (Ren et al, 2019). In our previous study, we have also preliminarily proved that PHF19 may act as an oncogene in ovarian cancer SKOV3 cells by using RNAi technology (Tao et al, 2018b), however, its exact role in the biological behaviors of ovarian cancer, especially its role in drug-resistance, needs to be further investigated.…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2020

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Ovarian cancer is one of the most common gynecological malignancies in women worldwide with a poor survival rate. We have previously reported that compound fuling granule (CFG), a traditional Chinese medicinal preparation used to treat ovarian cancer in China for over 20 years, significantly promotes cell cycle arrest, apoptosis, senescence, TGFb-induced invasion and migration, tumor growth, and distant metastasis in ovarian cancer cells. However, the underlying mechanisms are not clear. In the present study, we found that PHF19 expression in ovarian cancer cells positively correlated with their resistance ability to CFG. In addition, PHF19 overexpression increased the resistance of HEY-T30 and SKOV3 cells to CFG, while knockdown of PHF19 enhanced their sensitivity to CFG. Moreover, CFG significantly inhibited the expression of PHF19 both in mRNA and protein levels in these cells. Gain of function and loss of function experiments further proved that PHF19 is a crucial mediator involved in the ovarian cancer progression, including cell proliferation, invasion, migration, and stemness. Importantly, rescue the expression of PHF19 reverted CFG-induced suppression in ovarian cancer cell growth, EMT and stemness, while PHF19 knockdown accelerated CFG's anti-tumor effect. Overall, our results provide a series of evidence to reveal that PHF19 is critical suppressor for CFG's anti-tumor effect in ovarian cancer.

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PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation

Cited by 60 publications

References 79 publications

Multiple Myeloma DREAM Challenge Reveals Epigenetic RegulatorPHF19As Marker of Aggressive Disease

Multiple Myeloma DREAM Challenge Reveals Epigenetic RegulatorPHF19As Marker of Aggressive Disease

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

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

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