The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation

Maurus K, Hufnagel A, Geiger F, Graf S, Berking C, Heinemann A, Paschen A, Kneitz S, Stigloher C, Geissinger E, Otto C, Boßerhoff AK, Schartl M, Meierjohann S (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Oncogene Springer Nature

Book Volume: 36

Pages Range: 5110-5121

Journal Issue: 36

DOI: 10.1038/onc.2017.135

Abstract

The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.

Authors with CRIS profile

Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Klinikum der Universität München DE Germany (DE) Paul Ehrlich Institute / Paul-Ehrlich-Institut – Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel (PEI) DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE)

How to cite

APA:

Maurus, K., Hufnagel, A., Geiger, F., Graf, S., Berking, C., Heinemann, A.,... Meierjohann, S. (2017). The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation. Oncogene, 36(36), 5110-5121. https://doi.org/10.1038/onc.2017.135

MLA:

Maurus, K., et al. "The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation." Oncogene 36.36 (2017): 5110-5121.

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