The ubiquitin-like modifier FAT10 in cancer development

Aichem, Annette; Groettrup, Marcus

doi:10.1016/j.biocel.2016.07.001

Cited by 65 publications

(68 citation statements)

References 103 publications

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“…Under the catalytic action of E1 and E2 enzymes, FAT10 binds to substrates by FAT10ylation to form FAT10–substrate complexes, which enter the proteasome for degradation . Recently, there is accumulating evidence that FAT10 is up‐regulated in a variety of malignancies, including HCC, and that FAT10 overexpression is related to the prognosis of tumor . Our and other studies demonstrated that the increase of FAT10 expression could promote HCC cell proliferation .…”

Section: Discussionsupporting

confidence: 55%

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Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression

et al. 2018

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Recently, studies on transcriptome-proteome relationships have revealed mRNA/protein expression discordance for certain genes and speculated that protein posttranslational modification (PTM) may be involved. However, there is currently no evidence to support this hypothesis. Wnt-induced secreted protein-1 (WISP1) is the downstream target gene of β-catenin and plays an important role in tumorigenesis and progression, but the expression and role of WISP1 in different tumor types are controversial. Here, we first confirmed that WISP1 protein expression was significantly down-regulated in hepatocellular carcinoma (HCC) tissue and could be an independent predictor of poor prognosis for patients with HCC. In vivo and in vitro evidence was provided that WISP1 can suppress HCC cell proliferation. Further studies have found that low WISP1 protein expression was related to expression of human leukocyte antigen F locus adjacent transcript 10 (FAT10), a specific ubiquitin-like protein with both degradation and stabilization functions, which plays an important role in PTM. FAT10 overexpression facilitated WISP1 degradation by FAT10ylation to decrease WISP1 protein expression, thus promoting HCC proliferation. Interestingly, we found and demonstrated that FAT10 overexpression could result in WISP1 protein/mRNA expression discordance, with protein expression decreasing while mRNA expression increased. The underlying mechanism is that FAT10 exerts substrate stabilization and degradation functions simultaneously, while FAT10 overexpression promotes WISP1 mRNA expression by stabilizing β-catenin and directly degrades WISP1 protein. Conclusion: Our study demonstrated that overexpression of FAT10 results in expression discordance between WISP1 protein and mRNA, thereby promoting HCC progression by down-regulating WISP1 protein expression.

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Section: Discussionsupporting

confidence: 55%

“…Recently, multiple studies have found that abnormal FAT10 expression is closely related to the occurrence and development of tumors. FAT10 is highly expressed in various tumors, including hepatocellular carcinoma (HCC), and closely related to tumor proliferation, invasion and metastasis, and prognosis . Therefore, FAT10 is considered an oncogene.…”

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confidence: 99%

Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression

et al. 2018

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“…Top genes upregulated at least 2-fold in MLL- vs. AT1-TINT were for example, Scl30a2 –an epithelial Zn-transporter shown to be central for prostate function [45], Grhl3 –a factor that promotes cell migration and invasion [46], Ubd –a factor that promotes tumor growth and regulates immune responses [47], Il12rb2 –an immune regulatory factor [48], Plau –a stroma remodeling factor that promotes invasion and metastasis [49], Clu —an immune response- and apoptosis regulating factor [50], Efna5 –a factor suggested to be involved in prostate cancer [51], Parm1 –an androgen-regulated factor that influence apoptosis in prostate epithelial cells [52], Edn1 –a factor that promotes prostate cancer growth [53], Serpine1 –a factor regulating Plau (see above, [49]), Vtcn1 –a factor that restricts antitumor T-cell responses and is associated with metastasis [54], Mmp15 and Mmp7 –factors that promote stroma remodeling [55], Sulf1 –a factor involved in prostate development and cancer [56], S100a11 –a factor that promotes prostate cancer progression [57], Ctgf –a stroma stimulating factor [58], and Cyr61 –an angiogenic factor that is associated with prostate cancer progression [59]. …”

Section: Resultsmentioning

confidence: 99%

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

et al. 2017

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In order to grow and spread tumors need to interact with adjacent tissues. We therefore hypothesized that small but aggressive prostate cancers influence the rest of the prostate and regional lymph nodes differently than tumors that are more indolent. Poorly metastatic (Dunning AT1) or highly metastatic (Dunning MLL) rat prostate tumor cells were injected into the ventral prostate lobe of immunocompetent rats. After 10 days—when the tumors occupied about 30% of the prostate lobe and lymph node metastases were undetectable—the global gene expression in tumors, benign parts of the prostate, and regional iliac lymph nodes were examined to define tumor-induced changes related to preparation for future metastasis. The tumors induced profound effects on the gene expression profiles in the benign parts of the prostate and these were strikingly different in the two tumor models. Gene ontology enrichment analysis suggested that tumors with high metastatic capacity were more successful than less metastatic tumors in inducing tumor-promoting changes and suppressing anti-tumor immune responses in the entire prostate. Some of these differences such as altered angiogenesis, nerve density, accumulation of T-cells and macrophages were verified by immunohistochemistry. Gene expression alterations in the regional lymph nodes suggested decreased quantity and activation of immune cells in MLL-lymph nodes that were also verified by immunostaining. In summary, even when small highly metastatic prostate tumors can affect the entire tumor-bearing organ and pre-metastatic lymph nodes differently than less metastatic tumors. When the kinetics of these extratumoral influences (by us named TINT = tumor instructed normal tissue) are more precisely defined they could potentially be used as markers of disease aggressiveness and become therapeutic targets.

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“…And FAT10 was reported being up-regulated in several tumor types including tumors of the liver and colon [Lee et al, 2003][Lukasiak et al, 2008][Qing et al, 2011][Yan et al, 2010]. Although the mechanism of FAT10 promalignant function remains unclear, many researchers have re-ported that the expression of FAT10 increased with Akt, NF-κB/STAT3 [Gao et al, 2013][ Liu et al, 2014], CXCR4/7[Gao et al, 2013], MAD2 [Theng et al, 2014], p53 [Choi et al, 2014], and β-catenin/TCF4 [Aichem et al, 2016], in addition to its signal for proteasomal degradation [Schmidtke et al, 2014]. Previously, we reported that FAT10 plays an essential role in MDB formation and tumorigenesis [Oliva et al, 2008, 2010][French et al, 2012].…”

Section: Discussionmentioning

confidence: 99%

Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)

Jia

French

Tillman

et al. 2018

Experimental and Molecular Pathology

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Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths worldwide. Among others, non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the two major risk factors as both of them may develop cirrhosis and hepatocellular carcinoma (HCC) if left untreated. However, patients with NASH progress to HCC at a rate around 0.5% annually, while 3–10% ASH patients may progress to HCC annually. The present study is to demonstrate the molecular differences in oncogenesis pathway between NASH and ASH. By using immunofluorescence study and quantitating the fluorescence intensity morphometrically in liver biopsied specimens from NASH and ASH patients, the protein expression of candidate molecules within hepatocytes cytoplasm are studied, including two HCC-related molecules FAT10 and FOXO1, and one GPCR pathway related molecule ADRA2A. Compared with the control group patients, the expression levels of all the molecules were upregulated in the ASH group of patients(p<0.001 in all molecules), while FAT10 and ADRA2A were upregulated, FOXO1 did not change in the NASH group of patients.The most important finding is that compared with the ASH group of patients, the expression levels of all three molecules were significantly lower than in the NASH group of patients (p<0.001 in all molecules). These results confirmed our previous finding that there are significant differences of molecules change in ASH compared to NASH. Thus, we conclude that there are significantly different molecules and pathways involved during the pathogenesis of HCC development in ASH compared to NASH which could help explain why the tumorigenic rate is different in ASH and NASH.

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The ubiquitin-like modifier FAT10 in cancer development

Cited by 65 publications

References 103 publications

Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression

Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)

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