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Prp19 Arrests Cell Cycle Via Cdc5l in Hepatocellular Carcinoma Cells

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Prp19 Arrests Cell Cycle Via Cdc5l in Hepatocellular Carcinoma Cells International Journal of Molecular Sciences Article Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells Renzheng Huang 1, Ruyi Xue 1, Di Qu 2, Jie Yin 1,* and Xi-Zhong Shen 1,2,3,* 1 Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; [email protected] (R.H.); [email protected] (R.X.) 2 Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai 200032, China; [email protected] 3 Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China * Correspondence: [email protected] (J.Y.); [email protected] (X.-Z.S.); Tel.: +86-21-6404-1990 (ext. 2070) (J.Y. & X.-Z.S.); Fax: +86-21-6403-8038 (J.Y. & X.-Z.S.) Academic Editor: Akihiro Tamori Received: 16 January 2017; Accepted: 31 March 2017; Published: 7 April 2017 Abstract: Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. Recently, it has been identified as a candidate oncogene in hepatocellular carcinoma (HCC). However, the role of Prp19 in tumor biology is still elusive. Here, we reported that Prp19 arrested cell cycle in HCC cells via regulating G2/M transition. Mechanistic insights revealed that silencing Prp19 inhibited the expression of cell division cycle 5-like (Cdc5L) via repressing the translation of Cdc5L mRNA and facilitating lysosome-mediated degradation of Cdc5L in HCC cells. Furthermore, we found that silencing Prp19 induced cell cycle arrest could be partially resumed by overexpressing Cdc5L. This work implied that Prp19 participated in mitotic progression and thus could be a promising therapeutic target of HCC. Keywords: pre-mRNA processing factor 19; cell division cycle 5-like; cell cycle; translation; repressing the translation of mRNA; lysosome-mediated degradation 1. Introduction Liver cancer, about 70% to 90% of cases of which are hepatocellular carcinoma (HCC), is the fifth most common cancer in men and the seventh in women, and represents the second leading cause of cancer death among men and the sixth leading cause of cancer death among women worldwide [1]. Although surveillance in high-risk population allows diagnosis of HCC at an early stage, most cases still present at advanced and unresectable stage, and limited therapeutic options are available [2]. The development of HCC is a multistep process driving the progressive transformation of normal hepatocytes into highly malignant derivatives [3]. Among them, cell cycle deregulation is a common feature of human cancer [4]. Therefore, targeting the mitotic stage of the cell cycle may be an effective approach for cancer therapy [5]. The highly conserved Pre-mRNA processing factor 19 (Prp19)-associated complex (Prp19C) is a large multi-faceted protein complex that functions in diverse cellular processes, and novel roles of Prp19C are emerging [6]. Prp19C is a critical component of DNA repair and DNA damage checkpoint complexes, which is linked to deleterious consequences-cancer [7]. Prp19C is mainly composed of Prp19, cell division cycle 5-like (Cdc5L), pleiotropic regulator 1 and breast carcinoma amplified sequence 2 [8,9]. Among them, Prp19 forms a tetramer as a key architectural component for Prp19C stability [10]. Prp19 possesses E3 activity [11,12], and plays diverse roles in pre-mRNA splicing [13] and DNA damage response [14,15]. Despite disorders of these cellular events being linked to tumorigenesis, the potential role of Prp19 in HCC is still elusive. Cdc5L has been reported to play Int. J. Mol. Sci. 2017, 18, 778; doi:10.3390/ijms18040778 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 778 2 of 9 Int. J. Mol. Sci. 2017, 18, 778 2 of 9 a crucial role in mitotic progression. Overexpression of Cdc5L in mammalian cells causes shorter G2phase phase and and reduced reduced cell cell size size [16] [ 16and] and knockdown knockdown of Cdc5L of Cdc5L results results in dramatic in dramatic mitotic mitotic arrest arrest [17] and [17 ] andchromosome chromosome misalignments misalignments [18]. [Recently,18]. Recently, both Prp19 both Prp19and Cdc5L and Cdc5L have been have characterized been characterized to be tooverexpressed be overexpressed in HCC in tissues HCC tissuesand their and overexpressi their overexpressionon are positively are positively correlated correlatedwith poor prognosis with poor prognosis[17,19]. Considering [17,19]. Considering the importance the importance of Prp19 of Prp19and Cdc5L and Cdc5L within within this this complex, complex, the the relationship relationship betweenbetween them them deserves deserves toto bebe investigatedinvestigated inin HCC.HCC. InIn thisthis study,study, wewe demonstratedemonstrate thatthat thethe levelslevels of Prp19 and Cdc5L Cdc5L are are overexpressed overexpressed in in HCC HCC specimens,specimens, andand positivelypositively correlated correlated with with each each ot other.her. In In HCC HCC cells, cells, Prp19 Prp19 binds binds with with Cdc5L Cdc5L and andits itsdownregulation downregulation results results in inreduction reduction of of Cdc5L. Cdc5L. Mechanistic Mechanistic insights insights reveal reveal that that silencing silencing Prp19 Prp19 compromises translation activity of Cdc5L and facilitates lysosome-induced degradation of Cdc5L. compromises translation activity of Cdc5L and facilitates lysosome-induced degradation of Cdc5L. Furthermore, Prp19 knockdown arrests cell cycle at G2/M stage and targeting Prp19-induced mitotic Furthermore, Prp19 knockdown arrests cell cycle at G2/M stage and targeting Prp19-induced mitotic arrest is partially reversed by overexpressing Cdc5L in HCC cells. Taken together, the above findings arrest is partially reversed by overexpressing Cdc5L in HCC cells. Taken together, the above findings indicate that Prp19 takes part in the cell cycle regulation, rendering the potential of Prp19 as a indicate that Prp19 takes part in the cell cycle regulation, rendering the potential of Prp19 as a diagnotherapeutic target in HCC. diagnotherapeutic target in HCC. 2.2. Results Results 2.1.2.1. The The PositivePositive CorrelationCorrelation ofof Prp19Prp19 andand Cdc5LCdc5L in HCC ToTo investigate investigate thethe rolesroles ofof Prp19Prp19 andand Cdc5LCdc5L inin HCCHCC tissues, IHC staining was was performed performed with with tissuestissues from from 69 69 HCC HCC samples.samples. OurOur resultsresults demonstrateddemonstrated that, in in cancerous cancerous tissue, tissue, Prp19 Prp19 and and Cdc5L Cdc5L werewere both both mainlymainly locatedlocated at the the nucleus, nucleus, while while in in paracancerous paracancerous tissue tissue they they were were mainly mainly located located at atthe the cytoplasm, cytoplasm, and and this this phenomenon phenomenon was was confirmed confirmed by confocal by confocal laser laserscanning scanning (Figure (Figure S1). In S1). HCC In HCCtissues, tissues, Prp19 Prp19 and Cdc5L and Cdc5L were weremore moreabundant abundant (64/69 (64/69 for Prp19; for Prp19;63/69 for 63/69 Cdc5L) for Cdc5L)compared compared to paired to pairedparatumor paratumor tissue tissue(Figure (Figure 1A), which1A), which was further was further confirmed confirmed by western by western blot (13/14) blot (13/14) (Figure(Figure 1C). Sixty-1C). Sixty-ninenine HCC HCC clinical clinical specimens specimens were were subjected subjected to analyze to analyze the the correlation correlation between between Prp19 Prp19 and and Cdc5L. Cdc5L. Positive correlation between Prp19 level and Cdc5L expression was observed (R2 = 0.9146, p < 0.001; Positive correlation between Prp19 level and Cdc5L expression was observed (R2 = 0.9146, p < 0.001; Figure 1B). Figure1B). FigureFigure 1.1. TheThe Positive Positive Correlation Correlation of ofpre-mRNA pre-mRNA processi processingng factor factor 19 (Prp19) 19 (Prp19) and cell and division cell division cycle cycle5-like 5-like (Cdc5L) (Cdc5L) in hepatocellular in hepatocellular carcinoma carcinoma (HCC). (HCC).(A) Paracancerous (A) Paracancerous and Cancerous and Cancerous tissue sections tissue sectionsfrom HCC from patients HCC patients were marked were marked with antibodies with antibodies against againstPrp19 and Prp19 Cdc5L and Cdc5L(upper (upperpanel, panel,scale bar scale = bar100 = μ 100m); µLowerm); Lower panel panelindicated indicated the amplified the amplified view of view upper of panel upper (scale panel bar (scale = 20 μ barm); = (B 20) Theµm); positive (B) The positivecorrelation correlation of Prp19 of Prp19and Cdc5L and Cdc5L immu immunoactivitynoactivity score score in HCC in HCC tissues; tissues; (C) ( CPrp19) Prp19 and and Cdc5L Cdc5L expressionexpression inin tumortumor tissuetissue (C)(C) andand pairedpaired paratumorparatumor tissue (P) from HCC patient patient specimens specimens using using westernwestern blot. blot. Int. J. Mol. Sci. 2017, 18, 778 3 of 9 Int. J. Mol. Sci. 2017, 18, 778 3 of 9 2.2. Prp192.2. Prp19 Binds Binds with with Cdc5L Cdc5L and and Modulates Modulates Cdc5L Cdc5L ExpressionExpression in in HCC HCC Cells Cells BecauseBecause of the of the relationship relationship between between Prp19 Prp19 andand Cdc5L described described as asabove, above, we weproposed proposed that that Prp19 may infect the expression of Cdc5L. In vivo binding between Prp19 and Cdc5L was observed Prp19 may infect the expression of Cdc5L. In vivo binding between Prp19 and Cdc5L was observed in in Huh7 and SMCC-7721 cells. In contrast to normal mouse IgG, Cdc5L could be detected in the Huh7proteins
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