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MYC-Targeted WDR4 Promotes Proliferation, Metastasis, and Sorafenib Resistance by Inducing CCNB1 Translation in Hepatocellular Carcinoma

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MYC-Targeted WDR4 Promotes Proliferation, Metastasis, and Sorafenib Resistance by Inducing CCNB1 Translation in Hepatocellular Carcinoma www.nature.com/cddis ARTICLE OPEN MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma 1,2,3 1,2,3 1,2 1 1,2 1,2 1,2 1,2 1 Peng Xia , Hao Zhang , Kequan✉ Xu , Xiang Jiang ,✉ Meng Gao , Ganggang Wang , Yingyi Liu ,YeYao , Xi Chen , Weijie Ma1,2, Zhonglin Zhang1,2 and Yufeng Yuan 1,2 © The Author(s) 2021 Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment. Cell Death and Disease (2021) 12:691 ; https://doi.org/10.1038/s41419-021-03973-5 INTRODUCTION value of the m7G methyltransferase WDR4 in HCC remain Hepatocellular carcinoma (HCC) is one of the most common unknown. Therefore, in the present study, we first used The malignant tumours and the fourth leading cause of cancer deaths Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) worldwide [1]. The occurrence and development of HCC is a dataset and clinical data to assess WDR4 transcript levels in HCC complicated process involving a combination of aetiologies. and their impact on HCC patient prognosis. Mechanistically, we Although targeted therapy has achieved breakthroughs in recent provided evidence that WDR4 is transcriptionally activated by c- years, a large number of HCC patients still miss the best treatment MYC (MYC), facilitates cell proliferation and metastasis, and opportunities due to late diagnosis [2, 3]. Thus, there is an urgent enhances sorafenib resistance by promoting CCNB1 translation need to develop additional diagnostic markers and therapeutic in HCC. Thus, WDR4 is expected to be developed as a biomarker targets for HCC, which requires further research to determine the and potential therapeutic target for HCC patient prognosis. occurrence and development of HCC [4–6]. Since discovering the first form of RNA modification, more than 150 different RNA modifications in various RNA molecules have RESULTS been identified [7, 8], among which N7-methylguanosine (m7G) is WDR4 is highly expressed in HCC and associated with poor the most abundant modification in the 5′ cap of mRNA [9–11]. HCC patient prognosis With increased research in recent years, the m7G modification has Analysis of the TCGA-LIHC dataset showed that WDR4 transcript been shown to have extensive effects on tRNA, rRNA, and mRNA levels significantly increased in HCC (Fig. 1A). Kaplan−Meier and plays a vital role in various biological processes, including survival analysis revealed that WDR4 overexpression was sig- transcription elongation, pre-mRNA splicing, and mRNA transla- nificantly related to the poor prognosis of HCC patients (Fig. 1B). tion [12–14]. However, the genetic characteristics and prognostic UALCAN database analysis demonstrated that WDR4 transcript 1Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430062 Hubei, People’s Republic of China. 2Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430062 Hubei, People’s Republic of China. 3These authors contributed ✉ equally: Peng Xia, Hao Zhang. email: [email protected]; [email protected] Edited by N. Barlev Received: 20 March 2021 Revised: 22 June 2021 Accepted: 24 June 2021 Official journal of CDDpress P. Xia et al. 2 1234567890();,: Fig. 1 WDR4 expression is significantly increased in HCC. A Analysis of WDR4 transcript levels in HCC and normal tissues based on the TCGA database. B Overall and relapse-free survival curves of HCC patients. C WDR4 transcript levels are significantly related to HCC tumour stage and grade. D WDR4 expression in immortalized hepatocytes and six HCC cells. E, F Representative WDR4 expression and IHC results in 80 pairs of tumour tissues. *p < 0.05; **p < 0.01; ***p < 0.001. levels were significantly correlated with tumour grade and stage patients were determined by qRT-PCR, Western blotting, and (Fig. 1C). To investigate the roles of WDR4 in HCC progression, we immunohistochemical (IHC) staining. WDR4 protein levels were first evaluated the mRNA and protein levels of WDR4 in four HCC significantly increased in HCC (Fig. 1E, F), while WDR4 mRNA levels cell lines (Hep-3B, Hep-G2, HCC-LM3, and Huh-7) and observed were positively correlated with tumour size, TNM stage, BCLC that they were upregulated compared to those observed in stage, PVTT, and lymph node metastasis (Table S1). More hepatocytes (L02 cells; Fig. 1D). Additionally, the WDR4 mRNA and importantly, univariate and multivariate analyses of clinicopatho- protein levels in tumours and adjacent normal tissues of 80 HCC logical characteristics revealed that high WDR4 expression in HCC Cell Death and Disease (2021) 12:691 P. Xia et al. 3 A B Huh-7 HCC-LM3 Huh-7 HCC-LM3 1 1 A -NC kDa i-NC iRNA2 s siRN s si siRNAsiRNA2 45 WDR4 36 GAPDH Huh-7 HCC-LM3 Huh-7 HCC-LM3 C Huh-7 HCC-LM3 si-NC WDR4 WDR4 si-NC WDR4 WDR4 siRNA1 siRNA2 siRNA1 siRNA2 D si--NC WDR4 siRNA1 WDR4 siRNA2 F + - - + - - si-NC - + - - + - siRNA1 si--NC WDR4 siRNA2 WDR4 siRNA1 kDa - - + - - + siRNA2 32 FL Caspase 3 19 CL Caspase 3 E 36 GAPDH si--NC WDR4 siRNA1 WDR4 siRNA2 21 P21 r mber u umbe N N Number 50 CDC25C FL2-A PE-A FL2-A PE-A FL2-A PE-A 55 CCNB1 si--NC WDR4 siRNA1 WDR4 siRNA2 36 GAPDH r mbe mber u Nu Number N Huh-7 HCC-LM3 FL2-A PE-A FL2-A PE-A FL2-A PE-A Fig. 2 WDR4 promotes HCC cell growth. A Knockdown of WDR4 expression in Huh-7 and HCC-LM3 cells by siRNA. B, C CCK-8 and colony formation assays showing the proliferation ability of Huh-7 and HCC-LM3 cells. D, E Flow cytometry results showing the effect of WDR4 knockdown on apoptosis and cell cycle progression in Huh-7 and HCC-LM3 cells. F The expression of genes related to the cell cycle and apoptosis was detected by Western blotting. *p < 0.05; **p < 0.01; ***p < 0.001. correlated with shorter survival (Table S2). These results indicate cell apoptosis (Fig. S1D, S1E). Subsequently, we further assessed that WDR4 is a promising candidate biomarker for the diagnosis whether WDR4 regulates cell cycle- and apoptosis-related factors. and prognosis of HCC. Western blot analysis showed that WDR4 knockdown significantly upregulated P21 and downregulated CDC25C and CCNB1 (G2/M WDR4 promotes HCC growth by inducing the G2/M cell cycle cyclin) protein levels. In addition, WDR4 knockdown significantly transition and inhibiting apoptosis downregulated full-length (FL) caspase3 and upregulated cleaved- To further investigate the biological significance of WDR4 in HCC, length (CL) caspase3 levels (Fig. 2F). These findings were supported we designed siRNA to knock-down WDR4 in Huh-7 and HCC-LM3 by the results obtained through using WDR4-overexpressing cells cells (Fig. 2A). The CCK-8 and clone formation assay results showed (Fig. S1F) and indicated that WDR4 affects HCC cell growth by that WDR4 knockdown inhibited cell proliferation (Fig. 2B, C). inducing the G2/M phase transition and inhibiting cell apoptosis. Moreover, flow cytometry analysis showed that WDR4 knockdown caused cell cycle arrest in the G2/M phase and apoptosis (Fig. 2D, E). WDR4 promotes HCC cell migration and invasion by To further confirm the oncogenic effect of WDR4 in HCC, we promoting EMT constructed Li-7 cells overexpressing WDR4 (Fig. S1A). As expected, In subsequent experiments, transwell and scratch wound-healing WDR4 overexpression promoted cell proliferation (Fig. S1B, S1C), assay results showed that WDR4 knockdown inhibited cell invasion induced the G2/M phase transition of the cell cycle, and inhibited and migration (Fig. 3A, B). Moreover, qRT-PCR and Western blot Cell Death and Disease (2021) 12:691 P. Xia et al. 4 Fig. 3 WDR4 promotes HCC invasion and migration through epithelial-mesenchymal transition (EMT). A After WDR4 knockdown, a scratch wound-healing motility assay was used to assess cell migration. B Transwell Matrigel invasion assay to measure the cell invasion ability. C qRT- PCR and Western blot results showed changes in EMT. D WDR4 knockdown in HCC-LM3, HCC-LM3R, Huh-7, and Huh-7R cells increases their sensitivity to sorafenib. E CCK-8 assay results showing the proliferation ability of HCC-LM3, HCC-LM3R, Huh-7, and Huh-7R cells.
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