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      SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling

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          Abstract

          Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion. Depletion SHARPIN increases YAP protein level and YAP/TEAD target genes, such as CTGF and CYR61 in ESCC. Immuno-precipitation assay shows that SHARPIN associates with YAP, promoting YAP degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Our study reveals a novel post-translational mechanism in modulating Hippo signaling in ESCC. Overexpression or activation of SHARPIN could be a promising strategy to target Hippo signaling for ESCC patients.

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          Genetic landscape of esophageal squamous cell carcinoma.

          Yi-Bo Gao, Zhao-Li Chen, Jia-Gen Li … (2014)
          Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.
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            SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.

            Fumiyo Ikeda, Yonathan Lissanu Deribe, Sigrid Skånland … (2011)
            SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
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              SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex.

              Fuminori Tokunaga, Tomoko Nakagawa, Masaki Nakahara … (2011)
              Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM, symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-κB essential modulator; also known as IKBKG). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-α- and CD40-mediated activation of NF-κB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-κB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-κB activation in various disorders.
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                Author and article information

                Contributors
                Lidong Wang
                Ting Zhuang
                Xiumin Li
                Journal
                Journal ID (nlm-ta): Neoplasia
                Journal ID (iso-abbrev): Neoplasia
                Title: Neoplasia (New York, N.Y.)
                Publisher: Neoplasia Press
                ISSN (Print): 1522-8002
                ISSN (Electronic): 1476-5586
                Publication date PMC-release: 26 December 2019
                Publication date Collection: February 2020
                Publication date (Electronic): 26 December 2019
                Volume: 22
                Issue: 2
                Pages: 76-85
                Affiliations
                [a ]Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
                [b ]Center for Cancer Research, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
                [c ]Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
                [d ]Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
                [e ]Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
                [f ]Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
                [g ]Henan Key Laboratory for Esophageal Cancer Research and State Key Laboratory for Esophageal Cancer Prevention & Treatment of The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
                Author notes
                [* ]Address all correspondence to: Xiumin Li, Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China. ldwang2007@ 123456126.com 77090993@ 123456qq.com lxm3029981@ 123456126.com
                [1]

                Aijia Zhang, Weilong Wang, Zhijun Chen, Dan Pang, and Xiaofeng Zhou contribute equally to this study.

                Article
                Publisher ID: S1476-5586(19)30339-2
                DOI: 10.1016/j.neo.2019.12.001
                PMC ID: 6939053
                PubMed ID: 31884247
                SO-VID: 904a2f15-a097-441e-af4a-ae74c67e2b98
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 17 August 2019
                Date revision received : 28 November 2019
                Date accepted : 1 December 2019
                Categories
                Subject: Original article

                Keywords: sharpin, shank-associated rh domain interacting protein,escc, esophageal squamous cell carcinoma,ubl, ubiquitin-like domain,nzf, npl4 zinc finger domain,emt, epithelial-mesenchymal transition,atcc, american type culture collection
                Data availability:
                Keywords: sharpin, shank-associated rh domain interacting protein, escc, esophageal squamous cell carcinoma, ubl, ubiquitin-like domain, nzf, npl4 zinc finger domain, emt, epithelial-mesenchymal transition, atcc, american type culture collection

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