Nuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanoma. Issue 12 (5th September 2022)

• Record Type: Journal Article
• Authors: Seefried, Felix; Haller, Lucia; Fukuda, Shinji; Thongmao, Aranya; Schneider, Nadja; Utikal, Jochen; Higashiyama, Shigeki; Bosserhoff, Anja Katrin; Kuphal, Silke
• Is Part Of: International journal of cancer. Volume 151:Issue 12(2022)
• Page Start: 2244
• Page End: 2264
• Publication Date: 2022-09-05
• Subjects: AREG (amphiregulin) -- heterochromatin -- melanoma -- resistance -- Vemurafenib; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34254
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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. Abstract : What's new? Depending on the cell type, AREG has been shown to play a tumor suppressive or oncogenic role. Its oncogenic function is mainly mediated through its extracellular binding and activation of EGFR. Here, the authors show for the first time that AREG localizes in the cytoplasm and more importantly in the nucleus of melanoma cells. Nuclear AREG is involved in the epigenetic reprogramming of melanoma cells to regulate a phenotype switch from proliferation to invasion and drug resistance independent from EGFR. Furthermore, the authors show that silencing of nuclear AREG helps to overcome Vemurafenib resistance.