Nuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanoma

dc.contributor.authorSeefried, Felix
dc.contributor.authorHaller, Lucia
dc.contributor.authorFukuda, Shinji
dc.contributor.authorThongmao, Aranya
dc.contributor.authorSchneider, Nadja
dc.contributor.authorUtikal, Jochen
dc.contributor.authorHigashiyama, Shigeki
dc.contributor.authorBosserhoff, Anja Katrin
dc.contributor.authorKuphal, Silke
dc.date.accessioned2022-11-25
dc.date.available2023-10-09T18:44:05Z
dc.date.created2022
dc.date.issued2022-11-25
dc.description.abstractAbstract AMPHIREGULIN (AREG) is a multifaceted molecule, which acts not only as an extracellular ligand for EGF receptor (EGFR), but also as an intracellular signaling molecule. It remains elusive, however, whether AREG has a tumor suppressive or oncogenic role in melanoma. Here, we found that several melanoma cell lines express AREG, but the expression does not correlate with that of EGFR. Recombinant AREG and the neutralizing antibody experiments showed that intracellular AREG plays an important role in melanoma, implying a divergent function of AREG in addition to the role as a ligand for EGFR. Further investigation of this mechanism revealed that particularly nuclear‐localized AREG regulates IGF‐1R, P21 (Cip1/Waf1), TP53 and JARID1B protein accumulation in the nucleus. Furthermore, manipulation of nuclear AREG levels has influence on heterochromatin condensation (HP1beta, SETDB1) and trimethylation of histones H3K9 and H3K4. As these molecules correspond to previously identified markers for slow‐cycling drug resistant cells, we speculate that nuclear AREG predisposes cells to resistance to therapy. According to the hypothesis, we detected the accumulation of AREG in the nucleus of SK‐Mel‐28‐VR, which was cultured under Vemurafenib (VR) selection pressure, and this correlates with JARID1B expression. Here, knockdown of AREG makes the previously resistant cells more sensitive to VR treatment, resulting in inhibited proliferation. Taken together, we suggest that nuclear AREG affects a slow‐cycling phenotype and increases resistance to VR, raising a possibility that AREG might be a potential therapeutic target for resistance in melanoma.en
dc.format.extent20
dc.identifier.citationInternational Journal of Cancer 151.12 (2022): 2244-2264. <https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.34254>
dc.identifier.doihttps://doi.org/10.1002/ijc.34254
dc.identifier.opus-id20968
dc.identifier.urihttps://open.fau.de/handle/openfau/20968
dc.identifier.urnurn:nbn:de:bvb:29-opus4-209685
dc.language.isoen
dc.publisherJohn Wiley & Sons, Inc.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.de
dc.subjectAREG (amphiregulin)
dc.subjectheterochromatin
dc.subjectmelanoma
dc.subjectresistance
dc.subjectVemurafenib
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleNuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanomaen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.date.prevpublished2022-10-20
local.document.pageend2264
local.document.pagestart2244
local.journal.issue12
local.journal.titleInternational Journal of Cancer
local.journal.volume151
local.publisherplaceHoboken, USA
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.importimport
local.subject.sammlungUniversität Erlangen-Nürnberg / Eingespielte Open Access Artikel / Eingespielte Open Access Artikel 2022
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