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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2018 | Research

PHD-finger domain protein 5A functions as a novel oncoprotein in lung adenocarcinoma

Authors: Yan Yang, Jian Zhu, Tiantian Zhang, Jing Liu, Yumei Li, Yue Zhu, Lingjie Xu, Rui Wang, Fang Su, Yurong Ou, Qiong Wu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Abstract

Background

PHD-finger domain protein 5A (PHF5A) is a highly conserved small transcriptional regulator also involved in pre-mRNA splicing; however, its biological functions and molecular mechanisms in non-small cell lung cancer (NSCLC) have not yet been investigated. The purpose of this study was to determine the functional relevance and therapeutic potential of PHF5A in lung adenocarcinoma (LAC).

Methods

The expression of PHF5A in LAC tissues and adjacent non-tumor (ANT) tissues was investigated using immunohistochemistry of a tissue microarray, qRT-PCR, western blot and bioinformatics. The function of PHF5A was determined using several in vitro assays and also in vivo assay by lentiviral vector-mediated PHF5A depletion in LAC cell lines.

Results

PHF5A was highly upregulated in LAC tissues compared with the ANT counterparts, and closely associated with tumor progression and poor patient prognosis. These results were further confirmed by findings of the TCGA database. Moreover, functional studies demonstrated that PHF5A knockdown not only resulted in reduced cell proliferation, increased cell apoptosis, and cell cycle arrest, but also suppressed migration and invasion in LAC cells. PHF5A silencing was also found to inhibit LAC tumor growth in nude mice. Microarray and bioinformatics analyses revealed that PHF5A depletion led to dysregulation of multiple tumor signaling pathways; selected factors in key signaling pathways were verified in vitro.

Conclusions

The data suggest for the first time that PHF5A is an oncoprotein that contributes to LAC progression by regulating multiple signaling pathways, and may constitute a prognostic factor and potential new therapeutic target in NSCLC.

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Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed

Cheng TY, Cramb SM, Baade PD, et al. The international epidemiology of lung Cancer: latest trends, disparities, and tumor characteristics. J Thorac Oncol. 2016;11:1653–71.CrossRefPubMedPubMedCentral

Chen Z, Fillmore CM, Hammerman PS, et al. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14:535–46.CrossRefPubMedPubMedCentral

Trappe R, Ahmed M, Glaser B, et al. Identification and characterization of a novel murine multigene family containing a PHD-finger-like motif. Biochem Biophys Res Commun. 2002;293:816–26.CrossRefPubMed

Oltra E, Pfeifer I, Werner R. Ini, a small nuclear protein that enhances the response of the connexin43 gene to estrogen. Endocrinology. 2003;144:3148–58.CrossRefPubMed

Will CL, Urlaub H, Achsel T, et al. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002;21:4978–88.CrossRefPubMedPubMedCentral

Rzymski T, Grzmil P, Meinhardt A, et al. PHF5A represents a bridge protein between splicing proteins and ATP-dependent helicases and is differentially expressed during mouse spermatogenesis. Cytogenet Genome Res. 2008;121:232–44.CrossRefPubMed

Teng T, Tsai JH, Puyang X, et al. Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex. Nat Commun. 2017;8:15522.CrossRefPubMedPubMedCentral

Trappe R, Schulze E, Rzymski T, et al. The Caenorhabditis elegans ortholog of human PHF5a shows a muscle-specific expression domain and is essential for C. Elegans morphogenetic development. Biochem Biophys Res Commun. 2002;297:1049–57.CrossRefPubMed

10.

Buckley SM, Aranda-Orgilles B, Strikoudis A, et al. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell. 2012;11:783–98.CrossRefPubMedPubMedCentral

11.

Strikoudis A, Lazaris C, Trimarchi T, et al. Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol. 2016;18:1127–38.CrossRefPubMedPubMedCentral

12.

Oltra E, Verde F, Werner R, et al. A novel RING-finger-like protein Ini1 is essential for cell cycle progression in fission yeast. J Cell Sci. 2004;117:967–74.CrossRefPubMed

13.

Hubert CG, Bradley RK, Ding Y, et al. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. Genes Dev. 2013;27:1032–45.CrossRefPubMedPubMedCentral

14.

Falck E, Klinga-Levan K. Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer. Cancer Cell Int. 2013;13:43.CrossRefPubMedPubMedCentral

15.

Edge S, Byrd DR. Compton CC eds, et al. AJCC Cancer staging manual. New York: Springer; 2011.

16.

Wu Q, Wang R, Yang Q, et al. Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget. 2013;4:1999–2009.PubMedPubMedCentral

17.

Nabzdyk CS, Chun M, Pradhan L, et al. High throughput RNAi assay optimization using adherent cell cytometry. J Transl Med. 2011;9:48.CrossRefPubMedPubMedCentral

18.

Yang Y, Qin SK, Wu Q, et al. Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition. Oncol Rep. 2014;31:540–50.CrossRefPubMed

19.

McGonnell IM, Green CR, Tickle C, et al. Connexin43 gap junction protein plays an essential role in morphogenesis of the embryonic chick face. Dev Dyn. 2001;222:420–38.CrossRefPubMed

20.

Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.CrossRefPubMed

21.

Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett. 2012;326:191–8.CrossRefPubMed

22.

Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23:824–54.CrossRefPubMed

23.

Phillips LS, Pao CI, Villafuerte BC. Molecular regulation of insulin-like growth factor-I and its principal binding protein, IGFBP-3. Prog Nucleic Acid Res Mol Biol. 1998;60:195–265.CrossRefPubMed

24.

Lee KW, Ma L, Yan X, et al. Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77. J Biol Chem. 2005;280:16942–8.CrossRefPubMed

25.

Cazanave SC, Elmi NA, Akazawa Y, et al. CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol. 2010;299:G236–43.CrossRefPubMedPubMedCentral

26.

Upton JP, Austgen K, Nishino M, et al. Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress. Mol Cell Biol. 2008;28:3943–51.CrossRefPubMedPubMedCentral

27.

McCullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249–59.CrossRefPubMedPubMedCentral

28.

Wang G, Chan CH, Gao Y, et al. Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. Chin J Cancer. 2012;31:169–77.CrossRefPubMedPubMedCentral

29.

Zheng N, Zhou Q, Wang Z, et al. Recent advances in SCF ubiquitin ligase complex: clinical implications. Biochim Biophys Acta. 2016;1866:12–22.PubMedPubMedCentral

30.

Hung WC, Tseng WL, Shiea J, et al. Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 2010;288:156–61.CrossRefPubMed

31.

Reichert M, Saur D, Hamacher R, et al. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007;67:4149–56.CrossRefPubMed

32.

Lin HK, Wang G, Chen Z, et al. Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 2009;11:420–32.CrossRefPubMedPubMedCentral

33.

Gao D, Inuzuka H, Tseng A, et al. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol. 2009;11:397–408.CrossRefPubMedPubMedCentral

34.

Mehta HH, Gao Q, Galet C, et al. IGFBP-3 is a metastasis suppression gene in prostate cancer. Cancer Res. 2011;71:5154–63.CrossRefPubMedPubMedCentral

Title: PHD-finger domain protein 5A functions as a novel oncoprotein in lung adenocarcinoma
Authors: Yan Yang
Jian Zhu
Tiantian Zhang
Jing Liu
Yumei Li
Yue Zhu
Lingjie Xu
Rui Wang
Fang Su
Yurong Ou
Qiong Wu
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-018-0736-0

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Abstract

Background

Methods

Results

Conclusions

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