1. ¹INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes, France
2. ²Université de Nantes, UFR Médecine, IFR26, Institut de Biologie, Nantes, France
3. ³PIMESP, Nantes, France
4. ⁴Unit of Skin Cancer, CHU de Nantes, Nantes, France
5. ⁵Laboratoire de Biochimie, CHU de Nantes, Nantes, France

Correspondence: Dr A Godard or Dr F Blanchard, INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, 9 Quai Moncousu, 44035 Nantes cedex 1, France. E-mails: agodard@nantes.inserm.fr; frederic.blanchard@univ-nantes.fr

⁶Current address: INSERM, ERI7, 1 rue Gaston Veil, 44035 Nantes cedex 1, France.

Received 28 March 2006; Revised 6 June 2006; Accepted 26 June 2006; Published online 7 August 2006.

Abstract

Oncostatin M (OSM) is an interleukin-6 (IL-6) type cytokine originally described by its capacity to inhibit melanoma proliferation in vitro. Here, the mechanisms involved in resistance to growth inhibition by OSM were analysed for the first time on a large panel of metastatic melanoma cell lines. OSM resistance did not strictly correlate with IL-6, interferon- or tumor necrosis factor- resistance. Rather, it correlated with a specific loss of the OSM receptor- (OSMR) subunit, in conjunction with a lower level of histone acetylation in the OSMR promoter region. Treatment of various OSM-resistant melanoma cells with the histone deacetylase inhibitor Trichostatin A increased activity and histone acetylation of the OSMR promoter as well as expression of OSMR mRNA and protein, allowing OSM to activate the signal transducer and activator of transcription 3 (STAT3) and to inhibit proliferation. Other defects associated with OSM resistance were identified at the level of OSMR transcription or protein expression, as well as downstream of or parallel to STAT3 activation. Altogether, our results suggest a role for OSM in the prevention of melanoma progression and that metastatic melanoma cells could escape this growth control by the epigenetic silencing of OSMR.