Epigenetic developmental mechanisms underlying sex differences in cancer
Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang
Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang
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Review Series

Epigenetic developmental mechanisms underlying sex differences in cancer

Abstract

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, we review the epigenetics of sexual differentiation and its effect on cancer hallmark pathways throughout life. Specifically, we will touch on how sex differences in metabolism, immunity, pluripotency, and tumor suppressor functions are patterned through the epigenetic effects of imprinting, sex chromosome complement, X inactivation, genes escaping X inactivation, sex hormones, and life history.

Authors

Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang

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Figure 4

KDM6A and alterations in ATRX and EZHIP are associated with male-skewed cancers.

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KDM6A and alterations in ATRX and EZHIP are associated with male-skewed ...
(A) KDM6A (UTX) is a histone H3 lysine 27 di- and trimethylation (H3K27me2/3) demethylase that can lead to gene expression and serves as a tumor suppressor in bladder cancer in females. However, in mice, when Kdm6a is not present, downstream targets of the tumor suppressor p53, such as Cdnk1a and Perp, are not expressed. (B) ATRX interacts with DAXX and deposits H3.3 histone marks that cause chromatin compaction and inhibition of the ALT pathway. ATRX is mutated in some cancers including glioblastoma and oligodendroglioma that occur more often in males, and this leads to an upregulation of the ALT pathway in tumor cells, which can then cause tumor progression. (C) EZHIP interacts with the EZH2 subunit of PRC2 through its active site, causing loss of H3K27me3 levels, which can lead to gene expression. However, increased levels of H3K27me3 are observed at the CDKN2A locus in PFA ependymomas expressing EZHIP that suppress CDKN2A expression, thus lowering tumor suppressor function.