H. Shen

Histone lysine demethylases in mammalian embryonic development

Post-translational modifications, such as methylation, acetylation and phosphorylation, of histone proteins play important roles in regulating dynamic chromatin structure. Histone demethylation has become one of the most active research areas of epigenetics in the past decade. To date, with the exception of histone H3 lysine 79 methylation, the demethylases for all major lysine methylation sites have been discovered. These enzymes have been shown to be involved in various biological processes, with embryonic development being an exciting emerging area. This review will primarily discuss the involvement of these demethylases in the regulation of mammalian embryonic development, including their roles in embryonic stem cell pluripotency, primordial germ cell (PGC) formation and maternal-to-zygotic transition.

PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression

Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. ©2018 AACR.