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Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous

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Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. #CANCER RESEARCH CAN-18-1495-AT, Revised version R2. Loss of TRIM29 alters keratin distribution to promote cell invasion in squamous cell carcinoma 1, *Teruki Yanagi, 2Masashi Watanabe, 1Hiroo Hata, 1Shinya Kitamura, 1Keisuke Imafuku, 3Hiroko Yanagi, 3Akihiro Homma, 4, 5Lei Wang, 6Hidehisa Takahashi, 1Hiroshi Shimizu, 2, *Shigetsugu Hatakeyama Departments of 1Dermatology, 2Biochemistry, 3Otolaryngology - Head and Neck Surgery, and 4Cancer Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University; 5Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University; 6Department of Molecular Biology, Yokohama City University Graduate School of Medical Science *Correspondence and requests for materials should be addressed to T. Y. ([email protected]) or S. H. ([email protected]). Conflicts of Interest The authors have no conflicts of interest to declare. Word count: Abstract 199 words, Text 5000 words References: 36 Tables: 0, Figures: 7, Supplemental Figures: 18, Supplemental Table: 1 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Short title: TRIM29 in squamous cell carcinoma Abbreviations: TRIM: tripartite motif-containing protein SCC: squamous cell carcinoma EMT: epithelial mesenchymal transition SPC: sphingosylphosphorylcholine IP: immunoprecipitation IS: immunoscore Significance: Findings identify TRIM29 as a novel diagnostic and prognostic marker in stratified epithelial tissues. 2 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated. Here we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immunoprecipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29-keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics. 3 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Tripartite motif (TRIM) family proteins have various functions in cellular processes, including intracellular signaling, cell development, apoptosis, protein quality control, and carcinogenesis (1). TRIM family proteins have conserved domains that include a RING, a B box type 1, a B box type 2, and a coiled-coil region. Although most TRIM family proteins have a RING domain, TRIM29 (also known as ataxia-telangiectasia group D complementing protein, or ATDC) lacks it (2). We previously showed that TRIM29 regulates the assembly of DNA repair proteins into damaged chromatin (3). TRIM29 interacts with BRCA1-associated surveillance complex, cohesion, DNA-PKcs, and components of the TIP60 complex, suggesting that TRIM29 functions as a scaffold protein in DNA damage response. Further, a study on TRIM29 knockout mice revealed TRIM29 to be a regulator for the activation of alveolar macrophages, the expression of type I interferons and the production of proinflammatory cytokines in the lungs (4). Moreover, TRIM29 has been reported to be overexpressed in several cancers, including lung (5), colorectal (6), and pancreatic cancers (7). A review of the expression of TRIM29 in many cancers revealed an important link between upregulated TRIM29 expression and poor prognosis in patients with malignant neoplasms (8). TRIM29 transgenic mice revealed that TRIM29 upregulates CD44 in pancreatic cancer cells via the activation of beta-catenin signaling, leading to the induction of epithelial mesenchymal transition (EMT) along with the expression of Zeb1 and Snail1 (9). These studies suggest that TRIM29 promotes 4 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. tumorigenesis and tumor progression in certain cancers. Conversely, in breast cancer, TRIM29 is often silenced due to aberrant gene hyper-methylation, which leads to the invasive behavior of breast cancers (10). Further, we previously reported that the TRIM29-positive cells disappear in prostate cancers (11). Thus, the expression levels of TRIM29 in cancers may depend on the cell/tissue types (12). Its role in stratified squamous epithelial cells/tumors has not been elucidated. Cutaneous squamous cell carcinoma (SCC) is a common cancer in Caucasian populations, accounting for 20-30% of skin malignancies (13). The risk of metastasis is low for most patients, not exceeding 5%; however, aggressive SCC is associated with high morbidity and mortality. Although cutaneous SCC can be treated by surgical removal, radiation, or chemotherapy, or by a combination of these therapies, the prognosis of patients with metastatic SCC is poor (14). Even in head and neck lesions, squamous cell carcinoma is the most common histological type. The risk factors of distant metastasis for head and neck SCC (HN-SCC) are related to age, the site of the primary cancer, local and/or regional extension, and histological grading (15). Patients with localized HN-SCC are treated with potentially curative therapy using treatment modalities that include surgery, radiation therapy, chemotherapy, and biologic therapy (16). The recurrence rate in early-stage HN-SCC ranges from 10 to 20%, and the recurrence rate in locally advanced HN-SCC exceeds 50%. Patients with metastatic HN-SCC have a poor prognosis with a median overall survival of less than 1 year (16). Therefore, identifying the molecular mechanisms involved in cutaneous, and head and 5 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. neck SCC pathogenesis is of vital clinical importance. In this study, we investigated the role of TRIM29 in the tumorigenesis/ progression of squamous cell carcinoma. Searches of public databases revealed that TRIM29 is highly expressed in stratified epithelial tissues, including in skin, and head and neck lesions. Immunohistochemically, TRIM29 has lower expression in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. DNA methylation analysis revealed the CpG lesion of TRIM29 in primary cutaneous SCC tumors to be aberrantly hypermethylated, whereas that in normal epidermis is not methylated. RNAi-mediated gene-knockdown of TRIM29 increases cancer cell migration and invasion; conversely, overexpression of TRIM29 inhibits these. Using non-biased comprehensive proteomics analysis, keratins and keratin-interacting protein FAM83H have been identified as TRIM29 interactors. Immunohistochemically, TRIM29 co-localizes with keratins in the cytoplasm, and the knockdown of TRIM29 alters the distribution of keratins. Furthermore, in primary tumors, lower levels of TRIM29 expression correlate with altered distribution patterns of keratins. Our findings reveal a critical function of TRIM29 in regulating keratin distribution as well as migration/invasion of SCC. 6 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 2, 2018; DOI: 10.1158/0008-5472.CAN-18-1495 Author manuscripts have been peer reviewed and accepted for publication but have not
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