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LINC00265 Promotes Colorectal Tumorigenesis Via ZMIZ2 and USP7-Mediated Stabilization of β-Catenin

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LINC00265 Promotes Colorectal Tumorigenesis Via ZMIZ2 and USP7-Mediated Stabilization of β-Catenin Cell Death & Differentiation (2020) 27:1316–1327 https://doi.org/10.1038/s41418-019-0417-3 ARTICLE LINC00265 promotes colorectal tumorigenesis via ZMIZ2 and USP7- mediated stabilization of β-catenin 1,2 1,2 1,2 1,2 1,2 1,2 3,4 3,4 Yahui Zhu ● Li Gu ● Xi Lin ● Kaisa Cui ● Cheng Liu ● Bingjun Lu ● Feng Zhou ● Qiu Zhao ● 1,2 1,2 Hongxing Shen ● Youjun Li Received: 9 December 2018 / Revised: 19 August 2019 / Accepted: 2 September 2019 / Published online: 17 September 2019 © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2019 Abstract Colorectal cancer (CRC) is the third most prevalent world cancer and oncogenic β-catenin is frequently dysregulated in CRC. Long noncoding RNAs (lncRNAs) play critical roles in colorectal tumorigenesis; however, the contributions of lncRNAs to human CRC remain largely unknown. In this study, we report that LINC00265 is upregulated and predicts poor clinical outcome in human patients with CRC. Depletion of LINC00265 and ZMIZ2 distinctly attenuates colorectal tumorigenesis in mice. Mechanistically, LINC00265 augments ZMIZ2 expression by acting as an endogenous sponge against several miRNAs, which directly target ZMIZ2 expression. Moreover, ZMIZ2 recruits the enzyme USP7, which β β 1234567890();,: 1234567890();,: deubiquitylates and stabilizes -catenin, thereby facilitating colorectal tumorigenesis. In addition, -catenin mediates LINC00265 and ZMIZ2 oncogenic phenotypes. Taken together, the LINC00265-ZMIZ2-β-catenin signaling axis plays a critical role in the colorectal tumorigenesis, which may be a potential therapeutic target. Introduction signaling, which control cell proliferation and survival, thus promoting colorectal tumorigenesis [3–5]. Colorectal cancer (CRC) imposes a pronounced cause of The WNT/β-catenin signaling is highly activated in CRC morbidity and mortality worldwide, and its pathogenesis is [5, 6]. Without WNT stimulation, cytoplasmic β-catenin is heterogeneous [1]. CRC risk is attributed to heritable factors, degraded by the destruction complex including adenoma- others such as inflammatory bowel disease and an unhealthy tous polyposis coli (APC), Axin, glycogen synthase kinase lifestyle and diet, which exacerbates CRC incidence [2]. (GSK)-3, casein kinase Iα (CKIα) and the E3-ubiquitin Oncogenic mutations in KRAS lead to deregulation of several ligase β-TrCP. β-catenin phosphorylation by GSK-3 and effector pathways, like phosphatidylinositol 3-kinase (PI3K) CKIα facilitates β-TrCP-mediated β-catenin ubiquitination and degradation in the proteasome [6, 7]. Upon WNT activation, WNT binds to the receptor Frizzled and associ- Edited by J.M. Hardwick ates AXIN with LRP5/6. This allows the destruction com- plex to fall apart and β-catenin to be stabilized. Supplementary information The online version of this article (https:// Subsequently, β-catenin translocates to the nucleus where it doi.org/10.1038/s41418-019-0417-3) contains supplementary material, which is available to authorized users. binds to the TCF1/LEF1 transcription factors and activates its transcriptional program [6, 7]. Genetic mutations in the * Youjun Li core components of Wnt/β-catenin signaling, like APC [email protected] mutation, lead to WNT signaling hyperactivation to drive 1 Hubei Key Laboratory of Cell Homeostasis, College of Life CRC occurrence [6, 7]. However, the concrete mechanism Sciences, Wuhan University, 430072 Wuhan, China of colorectal tumorigenesis is remained to be elucidated. fi 2 Medical Research Institute, School of Medicine, Wuhan Long noncoding RNA (lncRNA) is now de ned as the University, 430071 Wuhan, China long RNA transcripts with more than 200 nucleotides lacking 3 Department of Gastroenterology, Zhongnan Hospital of Wuhan protein encoding potential [8, 9]. Lots of evidence indicates University School of Medicine, 430071 Wuhan, China that lncRNA harbors critical impacts in regulating gene fi 4 Hubei Clinical Center and Key Laboratory for Intestinal and expression at levels of chromatin modi cation, transcriptional Colorectal Diseases, 430071 Wuhan, China and posttranscriptional regulation [8]. Many lncRNAs have LINC00265 promotes colorectal tumorigenesis via ZMIZ2 and USP7-mediated stabilization of β-catenin 1317 been identified to affect tumorigenesis. HOTAIR was one of all CRCs and 2106 genes were highly activated in CRCs the first lncRNAs reported to interact with polycomb repres- from matched normal and CRC tissues. In all, 1932 of the sive complex 2 subunits that regulated chromatin state, and above genes were upregulated in both groups with the promoted invasion and metastasis of breast and colon cancer mRNA abundance from 1512 of these genes being >10 by [10]. Long noncoding RNA UPAT was reported to interact RNA-SeqV2 analysis. Since survival rate is the most with and stabilize the epigenetic factor UHRF1 by interfering important parameter in patients prognosis, 302 such genes with its β-transducin repeat-containing protein-mediated ubi- were noted as being significantly negative correlated quitination to promote colon tumorigenesis [11]. LncGata6 (P < 0.05) between survival and mRNA level. Next, 268 was shown to recruit the NURF complex onto the Ehf pro- genes were identified to be essential genes in CRC cell lines moter to induce its transcription, which promotes Lgr4/5 from Project Achilles [22]. Intriguingly, LINC00265, the expression to enhance Wnt signaling activation and maintain unique lncRNA, was among these genes (Fig. 1a). There- stemness of intestinal stem cells and promote tumorigenesis fore, LNC00265 was chosen for further study. [12]. LINC00265 is located on human chromosome 7p14.1 To investigate the clinical significance of LINC00265 in and there is no mouse ortholog gene. Recently, LINC00265 CRC, TCGA, GSE25070 and CCLE databases were was shown to be upregulated in CRC and associated with checked. LINC00265 was upregulated in virtually all poor prognosis. Its deficiency decreases cell viability and tumors from matched normal and CRC tissues (Fig. 1b and glycolysis through directly binding to and negatively reg- Supplementary Fig. S1a, b). In CRC patients, those with ulating miR-216b-5p, while supplementation with ectopic tumor stage III/IV had high expression (Fig. 1c). Finally, miR-216b-5p significantly compromises the oncogenic patients with high expression usually had significantly poor activities of LINC00265 in CRC cells [13]. AML patients survival (Fig. 1d). These findings suggest that LINC00265 with higher serum LINC00265 expression suffer poorer overexpression is tightly related to the CRC occurrence and overall survival. LINC00265 contributes to AML migration may contribute to the other clinical character in CRC. and invasion via modulation of PI3K/AKT signaling [14]. ZMIZ1 and ZMIZ2 are PIAS-like proteins that are ori- LINC00265 inhibition retards CRC development ginally recognized as androgen receptor interacting proteins [15–17]. They both share a zinc-binding SP-RING/MIZ To evaluate the effects of LINC00265 on CRC develop- domain, which is conserved and mediates the interaction ment, we first identified LINC00265 to be an essential gene between Msx2 and PIASxβ. They also contain a C-terminal in colorectal cell lines from the dataset of Project Achilles transactivation domain that augments the AR-mediated tran- (Supplementary Fig. S2) [22]. Then shRNA-mediated scription [15]. ZMIZ1 has been shown to interact with P53 as inhibition of LINC00265 significantly retarded cell growth a transcriptional activator [18] and also cooperates with in vitro and in vivo xenograft growth, while it had no effect NOTCH1 to enhance c-Myc-driven T-ALL [19]. ZMIZ2 is a in two tested nontransformed cells (Fig. 2a–e). Altogether nuclear protein that most highly expresses in testis [15]andit these results indicate that LINC00265 is essential for CRC accelerates β-catenin-mediated transcription and augments growth. prostate cancer cell growth [20]. However, the specific mechanism is unclear. LINC00265 increases ZMIZ2 expression as a miRNA In this study, in a systematic screen, LINC00265 is upre- sponge gulated and highly correlated with poor clinical outcome in human patients with CRC. LINC00265 acts as an miRNA To illustrate the specific mechanism that LINC00265 sponge to enhance ZMIZ2 expression. Furthermore, ZMIZ2 exacerbates the CRC development, correlation analysis recruits USP7 to stabilize β-catenin, which facilitates color- between LINC00265 and other gene expression was con- ectal tumorigenesis. Altogether, the LINC00265-ZMIZ2-β- ducted in CRC from TCGA. Interestingly, among 25,000 catenin axis is indispensable for colorectal tumorigenesis. genes, ZMIZ2 expression was extremely positively related with LINC00265 in all CRC tissues (Fig. 3a–e). Then, we examined how LINC00265 regulated ZMIZ2 Results expression. LINC00265 inhibition decreased ZMIZ2 in both RNA and protein levels; in the meantime, inhibition of LINC00265 upregulation is predictive of poor clinical Dicer1, which is an essential miRNA processing enzyme, outcomes in human CRCs largely rescued and enhanced ZMIZ2 expression (Fig. 3f, g). We hypothesized that LINC00265 regulated ZMIZ2 through In order to find the hyperactive gene in colorectal tumor- miRNAs. As miRNAs are located mostly in cytoplasm, qPCR igenesis, we analyzed gene expression in CRC from TCGA assay implicated that LINC00265 accounted for more than database [21]. Interestingly, 2585 genes were upregulated in 60% in cytoplasm in HCT116, SW480 and RKO, and almost 1318 Y. Zhu et al. Fig. 1 LINC00265 upregulation is predictive
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