The Bateson-Dobzhansky-Muller (BDM) model describes negative epistatic interactions that occur between genes with a different evolutionary history to account for hybrid incompatibility and is a central theory explaining genetic mechanisms underlying speciation.,Since the early 1900 s when the BDM model was forwarded examples of BDM incompatibility have been described in only a few nonvertebrate cases.,This study reports the only vertebrate system, with clearly defined interacting loci, that supports the BDM model.,In addition, this study also poses that tumorigenesis serves as a novel mechanism that accounts for postzygotic isolation.,Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population.,Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility.,Interspecies hybridization between southern platyfish and green swordtails leads to lethal melanocyte tumorigenesis.,This occurs in hybrids with tumor incidence following progeny ratio that is consistent with two-locus interaction, suggesting melanoma development is a result of negative epistasis.,Such observations make Xiphophorus one of the only two vertebrate hybrid incompatibility examples in which interacting genes have been identified.,One of the two interacting loci has been characterized as a mutant epidermal growth factor receptor.,However, the other locus has not been identified despite over five decades of active research.,Here we report the localization of the melanoma regulatory locus to a single gene, rab3d, which shows all expected features of the long-sought oncogene interacting locus.,Our findings provide insights into the role of egfr regulation in regard to cancer etiology.,Finally, they provide a molecular explainable example of hybrid incompatibility.
Anthracycline chemotherapeutics, e.g. doxorubicin and daunorubicin, are active against a broad spectrum of cancers.,Their cytotoxicity is mainly attributed to DNA intercalation, interference with topoisomerase activity, and induction of double-stranded DNA breaks.,Since modification of anthracyclines can profoundly affect their pharmacological properties we attempted to elucidate the mechanism of action, and identify possible molecular targets, of bis-anthracycline WP760 which previously demonstrated anti-melanoma activity at low nanomolar concentrations.,We studied the effect of WP760 on several human melanoma cell lines derived from tumors in various development stages and having different genetic backgrounds.,WP760 inhibited cell proliferation (IC50 = 1-99 nM), impaired clonogenic cell survival (100 nM), and inhibited spheroid growth (≥300 nM).,WP760 did not induce double-stranded DNA breaks but strongly inhibited global transcription.,Moreover, WP760 caused nucleolar stress and led to activation of the p53 pathway.,PCR array analysis showed that WP760 suppressed transcription of ten genes (ABCC1, MTOR, IGF1R, EGFR, GRB2, PRKCA, PRKCE, HDAC4, TXNRD1, AKT1) associated with, inter alia, cytoprotective mechanisms initiated in cancer cells during chemotherapy.,Furthermore, WP760 downregulated IGF1R and upregulated PLK2 expression in most of the tested melanoma cell lines.,These results suggest that WP760 exerts anti-melanoma activity by targeting global transcription and activation of the p53 pathway and could become suitable as an effective therapeutic agent.,The online version of this article (doi:10.1007/s10637-017-0465-9) contains supplementary material, which is available to authorized users.