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Lncrna-FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling

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Lncrna-FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 LncRNA—FEZF1-AS1 promotes tumor proliferation and metastasis in 2 colorectal cancer by regulating PKM2 signaling 3 4 Zehua Bian1†, Jiwei Zhang1†, Min Li1, Yuyang Feng1,2, Xue Wang2, Jia Zhang1,2, Surui Yao1, 5 Guoying Jin1, Jun Du3, Weifeng Han3, Yuan Yin1, Shenglin Huang4, Bojian Fei3, Jian Zou5*, 6 Zhaohui Huang1,2* 7 8 1 Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, 9 China. 10 2 Cancer Epigenetics Program, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 11 214122, China. 12 3 Department of Surgical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 13 214062, China. 14 4 Institutes of Biomedical Sciences and Shanghai Cancer Center, Shanghai Medical College, 15 Fudan University, Shanghai, 200032. China. 16 5 Center of Clincical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, 17 Jiangsu, 214023, China. 18 † These authors contributed equally to this work. 19 20 * Correspondence author: Zhaohui Huang, Wuxi Cancer Institute, Affiliated Hospital of 21 Jiangnan University, 200 Huihe Road, Wuxi, 214062, China. Tel/Fax: 86-510-88682087; 22 E-mail: [email protected], [email protected]. Jian Zou, Center of Clincical 23 Research, Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi, 24 214023, China. Tel: 86-510-85350368; E-mail: [email protected]. 25 26 Running Title: Oncogenic function of FEZF1-AS1 in colorectal cancer 27 28 Keywords: Long non-coding RNA, FEZF1-AS1, Colorectal cancer, PKM2, STAT3 29 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 30 Grant sponsors: This study was partially supported by grants from the National Natural 31 Science Foundation of China (81672328, 81272299, 81772636 and 81572468), Natural 32 Science Foundation of Jiangsu Province (BK20150004 and BK20151108), Fundamental 33 Research Funds for the Central Universities (NOJUSRP51619B and JUSRP51710A), 34 Medical Key Professionals Program of Jiangsu Province (AF052141), Medical Innovation 35 Team Program of Wuxi (CXTP003), Hospital Management Centre of Wuxi (YGZXZ1401), 36 and National First-class Discipline Program of Food Science and Technology 37 (JUFSTR20180101) . 38 39 Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were 40 disclosed. 41 42 Manuscript notes: 43 Abstract: 234; 44 Main text: 4734; 45 Figures: 6; 46 Tables: 1; 47 References: 39; 48 Supplementary information file: 11 figures, 4 tables 49 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 50 Statement of Translational Relevance 51 Long non-coding RNA (lncRNA) expression aberration has been observed in almost all 52 human cancers, providing a group of potential diagnostic markers, prognostic factors and 53 therapeutic targets in tumorigenesis. Our research revealed extensive aberrant expression 54 of lncRNA in colorectal cancer (CRC) and showed that FEZF1 antisense RNA 1 55 (FEZF1-AS1), one of the top upregulated lncRNAs in CRC, functions as an oncogene by 56 promoting CRC cell growth and metastasis. FEZF1-AS1 could bind and increase the stability 57 of pyruvate kinase 2 (PKM2) protein, resulting in the activating of STAT3 signaling and the 58 increasing of aerobic glycolysis. High FEZF1-AS1 and PKM2 expression are associated with 59 poor prognoses in CRC patients, suggesting that they could serve as valuable prognostic 60 factors. Targeting FEZF1-AS1/PKM2 signaling appears to be a promising treatment for 61 CRC. 62 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 63 Abstract 64 Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, 65 FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer (CRC), was identified by 66 lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of 67 FEZF1-AS1 in CRC. 68 Experimental Design: LncRNA expression in CRC tissues was measured by lncRNA 69 microarray and qRT-PCR. The functional roles of FEZF1-AS1 in CRC were demonstrated by 70 a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and 71 luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1. 72 Results: We identified a series of differentially expressed lncRNAs in CRC using lncRNA 73 microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further 74 validation in two expanded CRC cohorts confirmed the upregulation of FEZF1-AS1 in CRC, 75 and revealed that increased FEZF1-AS1 expression is associated with poor survival. 76 Functional assays revealed that FEZF1-AS1 promotes CRC cell proliferation and metastasis. 77 Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 78 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased 79 cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic 80 glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated 81 STAT3 signaling. In addition, PKM2 was upregulated in CRC tissues and correlated with 82 FEZF1-AS1 expression and patient survival. 83 Conclusions: Together, these data provide mechanistic insights into the regulation of 84 FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its 85 stability. 86 87 88 89 90 91 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 92 Introduction 93 Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence and 94 mortality are increasing in China (1,2). The development and progression of CRC involve a 95 series of complex genetic and epigenetic changes (3). Recent findings have revealed that 96 ~98% of human genome transcripts are non-coding RNAs (ncRNAs) with limited or no 97 protein-coding capacity. Long ncRNAs (lncRNAs), greater than 200 nt in length, account for 98 most of the ncRNA family. An increasing number of studies have demonstrated that lncRNAs 99 play key roles in the development and progression of human cancers, including CRC (4-6). 100 Although several lncRNAs, such as UCA1, LINC00152 and PVT1, have been reported to 101 be aberrantly expressed in CRC and shown to regulate CRC tumorigenesis and progression 102 (7-10), the functions and mechanisms of most lncRNAs in CRC remain unknown. For 103 example, CCAL could promote CRC progression by activating the Wnt/β-catenin pathway 104 (10). Our previous studies revealed that UCA1 and LINC00152 function as oncogenes by 105 promoting tumor growth and chemoresistance in CRC (7,8). 106 In this study, we identified a series of lncRNAs with aberrant expression in CRC tissues 107 using lncRNA expression microarrays. Subsequent validation in two expanded CRC cohorts 108 confirmed that FEZF1 antisense RNA 1 (FEZF1-AS1) (previously named AK057037 or 109 LOC154860) is upregulated in more than 60% of CRC tissues and is associated with poor 110 survival. Functional analyses revealed that FEZF1-AS1 enhances CRC cell proliferation and 111 metastasis. Mechanistic studies revealed that FEZF1-AS1 promotes CRC tumorigenesis 112 and progression by binding to pyruvate kinase M2 (PKM2) and enhancing the STAT3 113 signaling and aerobic glycolysis (Warburg effect). Our data reveal the novel regulatory roles 114 of FEZF1-AS1 in STAT3 signaling and glycolysis via PKM2 in CRC, suggesting that 115 FEZF1-AS1 could be a potential new therapeutic target for CRC. 116 117 Materials and Methods 118 Cell lines and clinical samples 119 The CRC cell lines LoVo, Caco2, HT29, HCT8, HCT116 and SW480 were purchased from 120 American Type Culture Collection (ATCC) from 2008 to 2014. The cells were cultured Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2018; DOI: 10.1158/1078-0432.CCR-17-2967 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 121 following the instructions recommended by ATCC. These cells were characterized by 122 Genewiz Inc. (China) using short tandem repeat (STR) markers and were confirmed to be 123 mycoplasma-free (last tested in 2017). 124 Two CRC cohorts, comprising 108 and 138 human primary CRC tissues and their paired 125 adjacent noncancerous tissues (NCTs) were obtained from Affiliated Hospital of Jiangnan 126 University
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