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Review Article Polycomb Protein Family Member CBX7 Plays a Critical Role in Cancer Progression

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Review Article Polycomb Protein Family Member CBX7 Plays a Critical Role in Cancer Progression Am J Cancer Res 2015;5(5):1594-1601 www.ajcr.us /ISSN:2156-6976/ajcr0006941 Review Article Polycomb protein family member CBX7 plays a critical role in cancer progression Pierlorenzo Pallante1, Floriana Forzati1, Antonella Federico1, Claudio Arra2, Alfredo Fusco1,3 1Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS), Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, Via S. Pansini 5, 80131 Naples, Italy; 2Istituto Nazionale dei Tumori, Fondazione Pascale, Via M. Semmola, 80131 Naples, Italy; 3Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37-Centro, Rio de Janeiro, CEP 20231-050 RJ, Brazil Received February 10, 2015; Accepted April 13, 2015; Epub April 15, 2015; Published May 1, 2015 Abstract: CBX7 is a polycomb protein that participates in the formation of polycomb repressive complex 1. Apart from few exceptions, CBX7 expression is lost in human malignant neoplasias and a clear correlation between its downregulated expression and a cancer aggressiveness and poor prognosis has been observed. These findings in- dicate a critical role of CBX7 in cancer progression. Consistently, CBX7 is able to differentially regulate crucial genes involved in cancer progression and in epithelial-mesenchymal transition, as osteopontin and E-cadherin. Recent evidences indicate a role of CBX7 also in the modulation of response to therapy. In conclusion, CBX7 represents an important prognostic factor, whose loss of expression in general indicates a bad prognosis and a progression towards a fully malignant phenotype. Keywords: CBX7, cancer progression, polycomb group CBX7 and the polycomb group proteins the chromodomain, then controlling the expres- sion of multiple genes [1-3]. CBX7 belongs to the family of Chromobox pro- teins and takes part in the organization of the Alterations of this crucial PcG system are polycomb repressive complex 1 (PRC1). Pro- responsible of aberrant development programs teins of the polycomb group (PcG) operate in and developing of different types of carcinoma. the context of multiprotein complexes that are In fact, abnormal increased expression of either involved in the regulatory mechanism control- PRC1 or PRC2 triggers the aberrant silencing of ling cell fate during development, in both nor- corresponding target genes, finally leading to mal and pathogenic conditions, through the the appearance of a broad spectrum of carcino- silencing of development-related genes. In- mas [4, 5]. However, also the recruitment of deed, PcG proteins cooperate to establish tran- PcG complexes to genes, normally not under scriptional repressor elements of at least two their control, can induce formation of cancers. functionally distinct complexes: (a) the initia- In fact, it has been recently reported that the tion complex (PRC2), whose main principal ele- oncogenic transcription factor PML/RAR alpha ments are human EZH2, EED and SUZ12, and is able to recruit the PRC2 complex to genes (b) the maintenance complex (PRC1), contain- responsive to retinoic acid (RA), then playing a ing as central human proteins BMI1, CBX7, primary role in the development of acute promy- EDR, HPC and RNF2 [1-3]. In the PRC2 com- elocytic leukemia (APL) [6]. plex, EZH2 carries-on methyltransferase activi- ty on histone lysine residues (histone H3, tri- Aberrant expression of CBX7 in human methylation of lysine 27, H3K27me3), that is carcinomas essential for inducing transcriptional repres- sion and stable gene silencing. On the contrary, Expression levels of CBX7 have been found CBX7 is able to bind H3K27me3 sites, through decreased in most of the human malignant CBX7 in cancer progression neoplasias analyzed so far. CBX7 downregula- loss of expression was correlated with poor tion was initially reported in carcinomas of the prognosis [9]. Interestingly, CBX7 downregula- bladder: the expression analysis performed in tion was also associated with progression of 93 patients undergoing surgery for urothelial dysplasia since levels of CBX7 expression carcinoma revealed that expression levels of decreased as severity of dysplasia increased CBX7 mRNA gradually decreased going from [9]. Noteworthy, HMGA1 expression, that has superficial to invasive and, lastly, to muscle- been frequently reported associated to cancer invasive carcinomas [7]. Besides, the expres- progression, increases going from colonic pre- sion levels of CBX7 resulted significantly corre- malignant lesions to colonic carcinoma, with a lated with higher tumor grade, suggesting that mutual behavior if compared to CBX7 [15, 16]. decreased levels of CBX7 could be functionally related with the acquisition of an aggressive Similarly, a progressive decrease of CBX7 pro- phenotype in urothelial carcinomas [7]. Similar tein expression was observed in specific neo- findings were obtained when CBX7 expression plastic malignancies of pancreas [11]. In this levels were evaluated in thyroid [8], colorectal system, as observed in other carcinomas, the [9], breast [10], pancreas [11], lung carcinomas diminished expression of CBX7 resulted inter- [12] and glioblastoma [13]. connected with progression of pancreatic ade- nocarcinoma, being its expression abundant in In human thyroid carcinoma, CBX7 expression normal pancreatic tissue and progressively levels, evaluated by RT-PCR and immunohisto- decreased going from pancreatic intraepithelial chemistry, progressively declined with the loss neoplasias (PanINs) through invasive ductal of differentiation degree and increasing of neo- carcinoma, where CBX7 expression is com- plasia stage. In fact, CBX7 was quite abundant pletely lost [11]. Consistently, the retention of in normal thyroid cells, whereas it was almost CBX7 expression displayed a trend toward a undetectable in most of the undifferentiated better survival. anaplastic carcinoma (ATC) and present, but at lower levels with respect to normal thyroid, in As far as human lung carcinoma is concerned, well differentiated ones as papillary (PTC) and none of the samples analyzed expressed follicular (FTC) carcinomas [8]. CBX7 was found detectable quantity of CBX7 protein, whereas it decreased or absent in 68% of Hürthle adeno- was abundantly expressed in normal lung tis- mas, which are characterized by an aggressive sue. Interestingly, LOH was reported in 50% of phenotype if compared to the classic benign informative cases. Additionally, the expression follicular adenomas (FTA) [14]. Interestingly, of CBX7 was lost in the “normal” area surround- expression of CBX7 in Hürthle hyperplasias and ing carcinomas (non-pathological at the mor- FTA resulted comparable to that observed in phological evaluation) in 50% of the analyzed non pathological thyroid tissue, confirming the cases. Intriguingly, these cases showed also more aggressive phenotype of Hürthle adeno- LOH, suggesting that the decreased expression mas in comparison to non-Hürthle neoplasias of CBX7 could be involved in the transition of [14]. In addition, loss of heterozygosity at CBX7 epithelial lung cells toward a fully transformed locus occurred in 36.8% of PTC and in 68.7% of and malignant phenotype [12]. ATC. Moreover, the evaluation of CBX7 expres- sion in rat and mouse models of thyroid carci- Reduced CBX7 protein levels were also nogenesis confirmed that CBX7 decreased with observed in breast carcinomas with the lowest the malignancy of carcinomas. Indeed, CBX7 expression levels observed in the lobular histo- diminished in PTC developed by TRK and RET/ type [10]. The expression of CBX7 was also PTC3 transgenic mice, while was completely downregulated in most of the gastric and liver lacking in ATC developed by SV40 Large T mice carcinomas [17]. [8]. The Cancer Genome Atlas (TCGA, cancerge- The immunohistochemical analysis of a tissue nome.nih.gov) shows that several PcG mem- microarray (TMA) containing more than one bers are aberrantly expressed in glioblastoma thousand sporadic CRC lesions revealed that multiforme samples in comparison to normal CBX7 is also decreased or absent in a high brain, with the upregulation of CBX8, EZH2, number of CRC samples, in comparison to the PHC2 and PHF19, and downregulation of CBX6, non pathological colonic mucosa, and that the CBX7, EZH1 and RYBP. Intriguingly, decreasing 1595 Am J Cancer Res 2015;5(5):1594-1601 CBX7 in cancer progression of CBX7 levels progressively occurred with the the cbx7 dosage [18]. Intriguingly, similar increasing of astrocytoma grade, as assessed results have been observed in cbx7-/- embryon- by Western blot and RT-PCR analyses [13]. ic stem (ES) cells as far as is concerned the dif- Lastly, consulting of TCGA confirms that CBX7 ferentiation into adipocytes, whereas MEFs is generally underexpressed in various carcino- and human adipose-derived stem cells overex- ma tissues (central nervous system cancer, pressing CBX7 showed an opposite behavior colorectal, ALL, hepatocarcinoma, lung adeno- [18]. carcinoma, melanoma and sarcoma) if com- pared with corresponding normal ones. In addi- Regulation of CBX7 protein expression tion, CBX7 is expressed at higher levels in ER+ than ER- breast cancer and at lower levels in A critical role in regulating CBX7 expression is metastatic prostate cancer than primary ones played by the High Mobility Group A (HMGA) (TCGA, cancergenome.nih.gov). These results, proteins. The HMGA protein family consists of therefore, associate the loss of CBX7 expres- three proteins (HMGA1a, HMGA1b and HMGA2) sion with cancer progression
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