Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Glioblastoma | Primary research

Silencing expression of PHF14 in glioblastoma promotes apoptosis, mitigates proliferation and invasiveness via Wnt signal pathway

Authors: Shuai Wu, Chen Luo, Fengjiao Li, N. U. Farrukh Hameed, Qiuyan Jin, Jie Zhang

Published in: Cancer Cell International | Issue 1/2019

Login to get access

Abstract

Background

The plant homeodomain (PHD) finger protein 14 (PHF14) is a vital member of PHD finger protein families. Abnormal expression of PHF14 has been identified in various cancers and is known to be implicated in the pathogenesis of tumors. This study investigates the role and the underlying mechanisms of PHF14 in GBM (glioblastoma multiforme).

Methods

Tissue microarrays and public databases interrogation were used to explore the relationship between the expression of PHF14 and GBM. Three stable PHF14-silenced cell lines (U251, U87MG and A172) were constructed to assess the biological functions changes of GBM cells in vitro. In addition, tumorigenicity in vivo was also performed using U87MG cell line. To understand the mechanism of action of PHF14, RNA-Seq, qRT-PCR, Western blot, IC50 assay and subsequent pathway analysis were performed.

Results

Our results showed that the expression of PHF14 was upregulated in glioma, especially in GBM. Overexpression of PHF14 translated to poor prognosis in glioma patients. In vitro assays revealed that silencing expression of PHF14 in glioma cells inhibited migration, invasiveness and proliferation and promoted cell apoptosis. Animal assay further confirmed that over-expression of PHF14 was a dismal prognostic factor. Analysis based on RNA-Seq suggested a PHF14-dependent regulation of Wnt signaling networks, which was further validated by qRT-PCR, Western blot and IC50 analysis. In addition, the mRNA expression of several key markers of EMT (epithelial–mesenchymal transition) and angiogenesis was found to change upon PHF14 silencing.

Conclusions

Our data provide a new insight into the biological significance of PHF14 in glioma and its potential application in therapy and diagnosis.
Appendix
Available only for authorised users
Literature
1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedCrossRef
2.
Ostrom QT, Gittleman H, de Blank PM, Finlay JL, Gurney JG, McKean-Cowdin R, Stearns DS, Wolff JE, Liu M, Wolinsky Y, et al. American brain tumor association adolescent and young adult primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2016;18(Suppl 1):i1–50.PubMedCrossRef
3.
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–53.PubMedCrossRef
4.
Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):829–48.PubMedCrossRef
5.
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343(19):1350–4.PubMedCrossRef
6.
Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol. 2008;4(3):152–6.PubMedCrossRef
7.
Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF, et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014;14(2):92–107.PubMedPubMedCentralCrossRef
8.
Aasland R, Gibson TJ, Stewart AF. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem Sci. 1995;20(2):56–9.PubMedCrossRef
9.
Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature. 2006;442(7098):86–90.PubMedCrossRef
10.
Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D, Pena P, Lan F, Kaadige MR, et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature. 2006;442(7098):96–9.PubMedPubMedCentralCrossRef
11.
Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–7.PubMedPubMedCentralCrossRef
12.
Lan F, Collins RE, De Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y. Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature. 2007;448(7154):718–22.PubMedPubMedCentralCrossRef
13.
Reader JC, Meekins JS, Gojo I, Ning Y. A novel NUP98-PHF23 fusion resulting from a cryptic translocation t(11;17)(p15;p13) in acute myeloid leukemia. Leukemia. 2007;21(4):842–4.PubMedCrossRef
14.
Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008;9(4):370–6.PubMedPubMedCentralCrossRef
15.
Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, Chen X, Kojima K, Thung S, Bronson RT, et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell. 2014;25(2):196–209.PubMedPubMedCentralCrossRef
16.
Liu Y, Chen W, Gaudet J, Cheney MD, Roudaia L, Cierpicki T, Klet RC, Hartman K, Laue TM, Speck NA, et al. Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO’s activity. Cancer Cell. 2007;11(6):483–97.PubMedPubMedCentralCrossRef
17.
Hubert CG, Bradley RK, Ding Y, Toledo CM, Herman J, Skutt-Kakaria K, Girard EJ, Davison J, Berndt J, Corrin P, et al. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. Genes Dev. 2013;27(9):1032–45.PubMedPubMedCentralCrossRef
18.
Hiddingh L, Raktoe RS, Jeuken J, Hulleman E, Noske DP, Kaspers GJ, Vandertop WP, Wesseling P, Wurdinger T. Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis. Sci Rep. 2014;4:5260.PubMedPubMedCentralCrossRef
19.
Lu J, Ji H, Tang H, Xu Z. microRNA-124a suppresses PHF19 over-expression, EZH2 hyper-activation, and aberrant cell proliferation in human glioma. Biochem Biophys Res Commun. 2018;503(3):1610–7.PubMedCrossRef
20.
Huang Q, Zhang L, Wang Y, Zhang C, Zhou S, Yang G, Li Z, Gao X, Chen Z, Zhang Z. Depletion of PHF14, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure. Acta Biochim Biophys Sin. 2013;45(8):622–33.PubMedCrossRef
21.
Kitagawa M, Takebe A, Ono Y, Imai T, Nakao K, Nishikawa S, Era T. Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-alpha. J Biol Chem. 2012;287(33):27983–96.PubMedPubMedCentralCrossRef
22.
Park JE, Tse SW, Xue G, Assisi C, Maqueda AS, Ramon G, Low JK, Kon OL, Tay CY, Tam JP, et al. Pulsed SILAC-based proteomic analysis unveils hypoxia- and serum starvation-induced de novo protein synthesis with PHD finger protein 14 (PHF14) as a hypoxia sensitive epigenetic regulator in cell cycle progression. Oncotarget. 2019;10(22):2136–50.PubMedPubMedCentralCrossRef
23.
Miao L, Liu HY, Zhou C, He X. LINC00612 enhances the proliferation and invasion ability of bladder cancer cells as ceRNA by sponging miR-590 to elevate expression of PHF14. J Exp Clin Cancer Res. 2019;38(1):143.PubMedPubMedCentralCrossRef
24.
Akazawa T, Yasui K, Gen Y, Yamada N, Tomie A, Dohi O, Mitsuyoshi H, Yagi N, Itoh Y, Naito Y, et al. Aberrant expression of the PHF14 gene in biliary tract cancer cells. Oncol Lett. 2013;5(6):1849–53.PubMedPubMedCentralCrossRef
25.
Ivanov I, Lo KC, Hawthorn L, Cowell JK, Ionov Y. Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. Oncogene. 2007;26(20):2873–84.PubMedCrossRef
26.
Zhang L, Huang Q, Lou J, Zou L, Wang Y, Zhang P, Yang G, Zhang J, Yu L, Yan D, et al. A novel PHD-finger protein 14/KIF4A complex overexpressed in lung cancer is involved in cell mitosis regulation and tumorigenesis. Oncotarget. 2017;8(12):19684–98.PubMedPubMedCentral
27.
Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.PubMedPubMedCentralCrossRef
28.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.PubMedCrossRef
29.
Gusev Y, Bhuvaneshwar K, Song L, Zenklusen J, Fine H, Madhavan S. The REMBRANDT study, a large collection of genomic data from brain cancer patients. Sci Data. 2018;5(1):180158.PubMedCentralCrossRefPubMed
30.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.CrossRef
31.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102.PubMedPubMedCentralCrossRef
32.
33.
Barrett A, Santangelo S, Tan K, Catchpole S, Roberts K, Spencer-Dene B, Hall D, Scibetta A, Burchell J, Verdin E, et al. Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases. Int J Cancer. 2007;121(2):265–75.PubMedCrossRef
34.
Alhosin M, Sharif T, Mousli M, Etienne-Selloum N, Fuhrmann G, Schini-Kerth VB, Bronner C. Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. J Exp Clin Cancer Res. 2011;30:41.PubMedPubMedCentralCrossRef
35.
Foote MB, Papadopoulos N, Diaz LJ. Genetic classification of gliomas: refining histopathology. Cancer Cell. 2015;28(1):9–11.PubMedCrossRef
36.
Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372(26):2499–508.PubMedPubMedCentralCrossRef
37.
Franceschi S, Mazzanti CM, Lessi F, Aretini P, Carbone FG, La Ferla M, Scatena C, Ortenzi V, Vannozzi R, Fanelli G, et al. Investigating molecular alterations to profile short- and long-term recurrence-free survival in patients with primary glioblastoma. Oncol Lett. 2015;10(6):3599–606.PubMedPubMedCentralCrossRef
38.
Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD, Nusse R. Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci USA. 2008;105(44):16970–5.PubMedCrossRefPubMedCentral
39.
40.
Hu B, Wang Q, Wang YA, Hua S, Sauve CG, Ong D, Lan ZD, Chang Q, Ho YW, Monasterio MM, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167(5):1281–95.PubMedPubMedCentralCrossRef
41.
Busch AM, Johnson KC, Stan RV, Sanglikar A, Ahmed Y, Dmitrovsky E, Freemantle SJ. Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer. 2013;13:211.PubMedPubMedCentralCrossRef
42.
Brabletz T. To differentiate or not–routes towards metastasis. Nat Rev Cancer. 2012;12(6):425–36.PubMedCrossRef
43.
Kahlert UD, Maciaczyk D, Doostkam S, Orr BA, Simons B, Bogiel T, Reithmeier T, Prinz M, Schubert J, Niedermann G, et al. Activation of canonical WNT/beta-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. Cancer Lett. 2012;325(1):42–53.PubMedCrossRef
44.
Kahlert UD, Nikkhah G, Maciaczyk J. Epithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas. Cancer Lett. 2013;331(2):131–8.CrossRefPubMed
45.
Wysocka J, Allis CD, Duncan EM, Ilin S, Wang W, Patel DJ, Li H. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature. 2006;442(7098):91–5.PubMedPubMedCentralCrossRef
46.
Taverna SD, Ilin S, Rogers RS, Tanny JC, Lavender H, Li H, Baker L, Boyle J, Blair LP, Chait BT, et al. Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Mol Cell. 2006;24(5):785–96.PubMedPubMedCentralCrossRef
47.
Chignola F, Gaetani M, Rebane A, Org T, Mollica L, Zucchelli C, Spitaleri A, Mannella V, Peterson P, Musco G. The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation. Nucleic Acids Res. 2009;37(9):2951–61.PubMedPubMedCentralCrossRef
48.
Nacev BA, Feng L, Bagert JD, Lemiesz AE, Gao J, Soshnev AA, Kundra R, Schultz N, Muir TW, Allis CD. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature. 2019;567(7749):473–8.PubMedPubMedCentralCrossRef
49.
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–3.PubMedPubMedCentralCrossRef
50.
Li H, Liefke R, Jiang J, Kurland JV, Tian W, Deng P, Zhang W, He Q, Patel DJ, Bulyk ML, et al. Polycomb-like proteins link the PRC2 complex to CpG islands. Nature. 2017;549(7671):287–91.PubMedPubMedCentralCrossRef
51.
Deng Q, Hou J, Feng L, Lv A, Ke X, Liang H, Wang F, Zhang K, Chen K, Cui H. PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/beta-catenin axis. Cell Death Dis. 2018;9(11):1049.PubMedPubMedCentralCrossRef
52.
Casanova M, Preissner T, Cerase A, Poot R, Yamada D, Li X, Appanah R, Bezstarosti K, Demmers J, Koseki H, et al. Polycomblike 2 facilitates the recruitment of PRC2 polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells. Development. 2011;138(8):1471–82.PubMedPubMedCentralCrossRef
53.
Gu B, Sun P, Yuan Y, Moraes RC, Li A, Teng A, Agrawal A, Rheaume C, Bilanchone V, Veltmaat JM, et al. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation. J Cell Biol. 2009;185(5):811–26.PubMedPubMedCentralCrossRef
Metadata
Title
Silencing expression of PHF14 in glioblastoma promotes apoptosis, mitigates proliferation and invasiveness via Wnt signal pathway
Authors
Shuai Wu
Chen Luo
Fengjiao Li
N. U. Farrukh Hameed
Qiuyan Jin
Jie Zhang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-1040-6

Other articles of this Issue 1/2019

Cancer Cell International 1/2019 Go to the issue

Primary research

Bursopentin (BP5) induces G1 phase cell cycle arrest and endoplasmic reticulum stress/mitochondria-mediated caspase-dependent apoptosis in human colon cancer HCT116 cells

Primary research

A 3-circular RNA signature as a noninvasive biomarker for diagnosis of colorectal cancer

Primary research

PAX8 expression in high-grade serous ovarian cancer positively regulates attachment to ECM via Integrin β3

Primary research

Combined analysis and validation for DNA methylation and gene expression profiles associated with prostate cancer

Primary research

Overexpression of mircoRNA-137 inhibits cervical cancer cell invasion, migration and epithelial–mesenchymal transition by suppressing the TGF-β/smad pathway via binding to GREM1

Primary research

KLF8 overexpression promotes the growth of human lung cancer cells by promoting the expression of JMJD2A
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits