Histone Demethylase kdm5d Upregulation Drives Sex Differences in Colon Cancer

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC

Histone demethylase KDM5D drives sex-specific differences in colorectal cancer

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Counterfeit Commerce:Relations of Production, Distribution and Exchange

Study of the consumption of counterfeit products casts consumers as reflexive agents who knowingly break the law (through the consumption of illegal commodities). Because this analysis is pitched at the level of meaning rather than structural constraints, it produces a misleading view of reflexive counterfeit consumption as being motivated by resistance or the wish to escape from normative coercion. This paper contrasts with approaches that prefigure meaning in explaining counterfeit commerce by treating the trade as an unavoidable structural feature of capitalism. That is, the structural logic of capital accumulation inevitably creates a black market of counterfeit commerce. It is a parasitic form of illegal consumerism which mirrors conventional capitalist organization reproducing familiar dynamics of valued status differentiation