{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:18:53Z","timestamp":1790957933225,"version":"4.1.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T00:00:00Z","timestamp":1619913600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,2]],"date-time":"2021-05-02T00:00:00Z","timestamp":1619913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81874136"],"award-info":[{"award-number":["81874136"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>ITIH5, a member of the inter-\u03b1-trypsin inhibitory (ITI) gene family, acts as a putative tumour-suppressor gene in many cancers. However, its role and the regulatory mechanism in melanoma are still unclear. Here, we found that the expression of ITIH5 was decreased in melanoma tissues compared with normal skin tissues. Decreased expression of ITIH5 was correlated with clinicopathological features and predicted poor prognosis in patients with melanoma. Forced expression of ITIH5 significantly inhibited melanoma cell proliferation and metastasis in vitro and ex vivo while knockdown of ITIH5 expression enhanced the malignant behaviour of melanoma cells. In further mechanistic studies, we showed that p53 can directly bind to the promoter of ITIH5 and thus promotes transcription of ITIH5 in melanoma cells. Additionally, we found that ITIH5 interacted with Kr\u00fcppel-like factor 4 (KLF4) and inhibited its transcriptional activity. Collectively, our data not only identified a tumour-suppressive role of ITIH5 in melanoma but also revealed that upregulation of ITIH5 by p53 suppressed melanoma cell growth and migration likely by downmodulating the transcriptional activity of KLF4.<\/jats:p>","DOI":"10.1038\/s41419-021-03707-7","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T13:07:00Z","timestamp":1620047220000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["ITIH5, a p53-responsive gene, inhibits the growth and metastasis of melanoma cells by downregulating the transcriptional activity of KLF4"],"prefix":"10.1038","volume":"12","author":[{"given":"Jia","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengrong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingrong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-3564","authenticated-orcid":false,"given":"Chuanchun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,2]]},"reference":[{"key":"3707_CR1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394\u2013424 (2018).","journal-title":"CA Cancer J. Clin."},{"key":"3707_CR2","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1200\/JCO.2014.58.3377","volume":"33","author":"RH Andtbacka","year":"2015","unstructured":"Andtbacka, R. H. et al. Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780\u20132788 (2015).","journal-title":"J. Clin. Oncol."},{"key":"3707_CR3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S1470-2045(15)70076-8","volume":"16","author":"JS Weber","year":"2015","unstructured":"Weber, J. S. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375\u2013384 (2015).","journal-title":"Lancet Oncol."},{"key":"3707_CR4","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nrc2622","volume":"9","author":"DX Nguyen","year":"2009","unstructured":"Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274\u2013284 (2009).","journal-title":"Nat. Rev. Cancer"},{"key":"3707_CR5","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.semcancer.2020.06.004","volume":"71","author":"H Nystrom","year":"2021","unstructured":"Nystrom, H. Extracellular matrix proteins in metastases to the liver-composition, function and potential applications. Semin. Cancer Biol. 71, 134\u2013142 (2021).","journal-title":"Semin. Cancer Biol."},{"key":"3707_CR6","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1158\/2159-8290.CD-18-0193","volume":"9","author":"A Kaur","year":"2019","unstructured":"Kaur, A. et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 9, 64\u201381 (2019).","journal-title":"Cancer Discov."},{"key":"3707_CR7","doi-asserted-by":"crossref","first-page":"38079","DOI":"10.1074\/jbc.R300039200","volume":"279","author":"L Zhuo","year":"2004","unstructured":"Zhuo, L., Hascall, V. C. & Kimata, K. Inter-alpha-trypsin inhibitor, a covalent protein-glycosaminoglycan-protein complex. J. Biol. Chem. 279, 38079\u201338082 (2004).","journal-title":"J. Biol. Chem."},{"key":"3707_CR8","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1046\/j.1432-1327.1998.2520339.x","volume":"252","author":"F Bost","year":"1998","unstructured":"Bost, F., Diarra-Mehrpour, M. & Martin, J. P. Inter-alpha-trypsin inhibitor proteoglycan family\u2014a group of proteins binding and stabilizing the extracellular matrix. Eur. J. Biochem. 252, 339\u2013346 (1998).","journal-title":"Eur. J. Biochem."},{"key":"3707_CR9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.canlet.2003.09.011","volume":"204","author":"M Himmelfarb","year":"2004","unstructured":"Himmelfarb, M. et al. ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer. Cancer Lett. 204, 69\u201377 (2004).","journal-title":"Cancer Lett."},{"key":"3707_CR10","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/exd.12704","volume":"24","author":"S Huth","year":"2015","unstructured":"Huth, S. et al. Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) is overexpressed in inflammatory skin diseases and affects epidermal morphology in constitutive knockout mice and murine 3D skin models. Exp. Dermatol. 24, 663\u2013668 (2015).","journal-title":"Exp. Dermatol."},{"key":"3707_CR11","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000509371","volume":"33","author":"S Huth","year":"2020","unstructured":"Huth, S. et al. Inter-alpha-Trypsin Inhibitor Heavy Chain 5 (ITIH5) is a natural stabilizer of hyaluronan that modulates biological processes in the skin. Skin Pharmacol. Physiol. 33, 198\u2013206 (2020).","journal-title":"Skin Pharmacol. Physiol."},{"key":"3707_CR12","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/oby.2011.268","volume":"20","author":"A Anveden","year":"2012","unstructured":"Anveden, A. et al. ITIH-5 expression in human adipose tissue is increased in obesity. Obesity 20, 708\u2013714 (2012).","journal-title":"Obesity"},{"key":"3707_CR13","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/sj.onc.1210669","volume":"27","author":"J Veeck","year":"2008","unstructured":"Veeck, J. et al. The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. Oncogene 27, 865\u2013876 (2008).","journal-title":"Oncogene"},{"key":"3707_CR14","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/carcin\/bgt375","volume":"35","author":"M Rose","year":"2014","unstructured":"Rose, M. et al. Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours. Carcinogenesis 35, 727\u2013736 (2014).","journal-title":"Carcinogenesis"},{"key":"3707_CR15","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.4161\/epi.32089","volume":"9","author":"V Kloten","year":"2014","unstructured":"Kloten, V. et al. Epigenetic inactivation of the novel candidate tumor suppressor gene ITIH5 in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype. Epigenetics 9, 1290\u20131301 (2014).","journal-title":"Epigenetics"},{"key":"3707_CR16","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s13148-011-0043-5","volume":"2","author":"C Oing","year":"2011","unstructured":"Oing, C. et al. Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia. Clin. Epigenet. 2, 419\u2013423 (2011).","journal-title":"Clin. Epigenet."},{"key":"3707_CR17","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1080\/15592294.2015.1078049","volume":"10","author":"MM Dotsch","year":"2015","unstructured":"Dotsch, M. M. et al. Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients\u2019 outcome. Epigenetics 10, 903\u2013912 (2015).","journal-title":"Epigenetics"},{"key":"3707_CR18","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1002\/mc.22613","volume":"56","author":"J Dittmann","year":"2017","unstructured":"Dittmann, J. et al. Gene expression analysis combined with functional genomics approach identifies ITIH5 as tumor suppressor gene in cervical carcinogenesis. Mol. Carcinog. 56, 1578\u20131589 (2017).","journal-title":"Mol. Carcinog."},{"key":"3707_CR19","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-017-0610-2","volume":"16","author":"M Rose","year":"2017","unstructured":"Rose, M. et al. ITIH5 mediates epigenetic reprogramming of breast cancer cells. Mol. Cancer 16, 44 (2017).","journal-title":"Mol. Cancer"},{"key":"3707_CR20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/mc.22742","volume":"57","author":"M Rose","year":"2018","unstructured":"Rose, M. et al. ITIH5 induces a shift in TGF-beta superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death. Mol. Carcinog. 57, 167\u2013181 (2018).","journal-title":"Mol. Carcinog."},{"key":"3707_CR21","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10585-017-9840-3","volume":"34","author":"K Sasaki","year":"2017","unstructured":"Sasaki, K. et al. Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer. Clin. Exp. Metastasis 34, 229\u2013239 (2017).","journal-title":"Clin. Exp. Metastasis"},{"key":"3707_CR22","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41416-020-01093-z","volume":"124","author":"ED Young","year":"2021","unstructured":"Young, E. D. et al. Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5. Br. J. Cancer 124, 166\u2013175 (2021).","journal-title":"Br. J. Cancer"},{"key":"3707_CR23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1126\/science.1905840","volume":"253","author":"M Hollstein","year":"1991","unstructured":"Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49\u201353 (1991).","journal-title":"Science"},{"key":"3707_CR24","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s13046-018-0842-z","volume":"37","author":"D Zhang","year":"2018","unstructured":"Zhang, D. et al. Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression. J. Exp. Clin. Cancer Res. 37, 176 (2018).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"3707_CR25","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1038\/onc.2016.481","volume":"36","author":"M Riverso","year":"2017","unstructured":"Riverso, M., Montagnani, V. & Stecca, B. KLF4 is regulated by RAS\/RAF\/MEK\/ERK signaling through E2F1 and promotes melanoma cell growth. Oncogene 36, 3322\u20133333 (2017).","journal-title":"Oncogene"},{"key":"3707_CR26","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/nm.4400","volume":"23","author":"M Murgai","year":"2017","unstructured":"Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176\u20131190 (2017).","journal-title":"Nat. Med."},{"key":"3707_CR27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.ebiom.2019.01.021","volume":"40","author":"MJ Rane","year":"2019","unstructured":"Rane, M. J., Zhao, Y. & Cai, L. Krupsilonppel-like factors (KLFs) in renal physiology and disease. EBioMedicine 40, 743\u2013750 (2019).","journal-title":"EBioMedicine"},{"key":"3707_CR28","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/351453a0","volume":"351","author":"AJ Levine","year":"1991","unstructured":"Levine, A. J., Momand, J. & Finlay, C. A. The p53 tumour suppressor gene. Nature 351, 453\u2013456 (1991).","journal-title":"Nature"},{"key":"3707_CR29","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrm2147","volume":"8","author":"KH Vousden","year":"2007","unstructured":"Vousden, K. H. & Lane, D. P. p53 in health and disease. Nat. Rev. Mol. Cell Biol. 8, 275\u2013283 (2007).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"3707_CR30","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1097\/CMR.0b013e328347ee04","volume":"21","author":"A Knopf","year":"2011","unstructured":"Knopf, A. et al. Analysis of the functional integrity of the p53 tumor-suppressor gene in malignant melanoma. Melanoma Res. 21, 380\u2013388 (2011).","journal-title":"Melanoma Res."},{"key":"3707_CR31","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1097\/00008390-199504000-00004","volume":"5","author":"LE Sparrow","year":"1995","unstructured":"Sparrow, L. E., Soong, R., Dawkins, H. J., Iacopetta, B. J. & Heenan, P. J. p53 gene mutation and expression in naevi and melanomas. Melanoma Res. 5, 93\u2013100 (1995).","journal-title":"Melanoma Res."},{"key":"3707_CR32","doi-asserted-by":"crossref","first-page":"15840","DOI":"10.1073\/pnas.1019312108","volume":"108","author":"L Jin","year":"2011","unstructured":"Jin, L. et al. MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma. Proc. Natl Acad. Sci. USA 108, 15840\u201315845 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3707_CR33","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.molcel.2020.01.005","volume":"77","author":"MR Webster","year":"2020","unstructured":"Webster, M. R. et al. Paradoxical role for wild-type p53 in driving therapy resistance in melanoma. Mol. Cell 77, 681 (2020).","journal-title":"Mol. Cell"},{"key":"3707_CR34","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1038\/s41418-019-0458-7","volume":"27","author":"X Wang","year":"2020","unstructured":"Wang, X. et al. The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis. Cell Death Differ. 27, 1747\u20131764 (2020).","journal-title":"Cell Death Differ."},{"key":"3707_CR35","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.canlet.2019.11.012","volume":"469","author":"H He","year":"2020","unstructured":"He, H. et al. TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression. Cancer Lett. 469, 380\u2013389 (2020).","journal-title":"Cancer Lett."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03707-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03707-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03707-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T08:58:43Z","timestamp":1669971523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03707-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,2]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["3707"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03707-7","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,2]]},"assertion":[{"value":"28 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 April 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Animal research was carried out according to the National Institute of Health Guide for the Care and Use of Laboratory Animals under the approval of the Animal Research Committee of Dalian Medical University.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"438"}}