**3. Histone modification in ovarian cancer**

Chromatin modifying enzymes are altered in ovarian cancers beyond DNA methylation. High levels of H3K9 methyltransferase G9a, which adds histone methyl groups (H3K9) to promote the compact structure of chromatin and silence genes, have been associated with late-stage high-grade and serous ovarian cancer, as well as shorter survival in patients with ovarian cancer [18]. Genes marked by the chromatin modifications of activating H3K4me3 and silencing H3K27me3 are identified as "poised" or bivalent; these are not transcribed into embryonic stem cells but resolved as differentiated stem cells into active and transcribed (H3K4me3) or silenced and not transcribed (H3K27me3). In 499 high-grade serous ovarian cancers, compared to eight normal fallopian tube samples, these bivalent chromatin loci were silenced and included genes in the PI3K and TGF-beta signaling pathways. Stem-like cells of ovarian cancer and chemo-resistant cells of ovarian cancer have demonstrated increased silencing of these genes [19]. As previously mentioned, the gene encoding the ARID1A chromatin remodeler is mutated in over 50 percent of ovarian clear cell carcinomas. In a mouse model of ovarian cancer, Bitler et al. showed inhibiting EZH2 methyltransferase, which adds the H3K27me3 mark to silence gene expression, induced regression of ARID1A-mutated tumors. This occurred via PIK3IPI upregulation, an ARID1A and EZH2 target increased by EZH2 inhibition and inhibits PI3K/Akt oncogenic signaling [20].
