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Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-kB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment.

Keywords:Modular/integral product architecture Make/pseudo-make/buy sourcing strategy U.S. bicycle industry a b s t r a c tThe bulk of the product architecture and make-buy choice literature deals with product architecture changes from integral to modular form. This development is often associated with a firm's tendency to change from a make to a buy strategy. However, a few studies investigate the change of product architecture in the reverse direction -from modular to integral form -and the subsequent change in the firm sourcing decision from a buy to a make strategy. These studies hold to the presumption that a firm following a make strategy will outperform firms following a buy strategy in dealing with integral product architectures. Based on the knowledge-based view, we argue for the viability of a sourcing strategy between the pure make and buy strategies -a pseudo-make strategy. We also argue that as product architecture changes from a modular to integral form, firms adopting this pseudo-make strategy are likely to show better product performance than firms following a pure make or buy strategy due to the relative knowledge advantages of the pseudo-make strategy in dealing with the integral product architecture. We examine the impact of the make/pseudo-make/buy strategies on product performance in the U.S. bicycle derailleur and freewheel market from 1980 to 1992 and provide theoretical and managerial implications of our results. Our findings highlight an important distinction between the pseudo-make and make-buy strategies that has not previously been fully appreciated in the extant literature, and as a result increases our understanding of why some firms do not switch strategies from a buy to a make strategy when product architecture changes from modular to integral form as previously expected.

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The relationship between product architecture (PA) and a firm’s make or buy (M-B) sourcing decision has been a topic of interest over the past several years. However, the interplay between PA and a firm’s M-B decision and its impact on performance is still underexplored. This study draws on transaction cost economics and the knowledge-based view within the framework of the PA and sourcing strategy literature to develop a causal model concerning the relationship between PA and the M-B sourcing decision and its implication for technological and financial performance via an investigation of the bicycle freewheel and derailleur markets from 1980 to 1995. The study readily provides theoretical reasoning as to why firms should choose an M-B sourcing strategy in the context of integral-modular PAs. It also suggests the need for further theoretical and empirical investigation of the relationships between PA type and the M-B choice and of the resulting impact of the sourcing decision on performance.