The Histone Demethylase PHF8 Governs Retinoic Acid Response in Acute Promyelocytic Leukemia

Abstract

While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.

The G2/M Regulator Histone Demethylase PHF8 Is Targeted for Degradation by the Anaphase-Promoting Complex Containing CDC20

“…Therefore, PHF8 is likely to be important for the regulation of gene expression in a context-dependent manner. Consistent with this hypothesis, PHF8 acts as a transcriptional coactivator for retinoic acid receptor alpha (RAR␣) and is recruited to target genes upon retinoic acid induction (such as in the case of all trans-retinoic acid (ATRA) treatment in acute promyelocytic leukemia) (17,18). Notch activation also leads to the assembly of PHF8 and complex components on Notch target genes, which is important for the activation of key Notch genes, such as those for interleukin-7 receptor and DTX1 (19).…”

RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

“…Jhdm1f/PHF8 has recently been identified as a key regulator of ATRA response in acute promyelocytic leukemia cells. 42 Whether JHDM1F activity influences the methylation status of H3K9 or normal HSC fate decisions remains to be explored. In contrast, removal of the active H3K4me3 epigenetic mark, potentially by JARID1B, could repress transcription of "stemness" genes and favor lineage commitment ( Figure 7, lower panel).…”

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

“…Among these demethylases, plant homeodomain finger-containing protein 8 (PHF8, also termed KDM7B) is a ubiquitously expressed nuclear protein consisting of an N-terminal plant homeodomain, which recognizes and binds histone H3 lysine 4 tri-methyl (H3K4me3) bearing nucleosomes at transcription start sites (6), and a JmjC domain catalyzing the removal of the methyl moieties from H3K9me1/2, H4K20me1, or H3K27me2 (7)(8)(9)(10). Specifically, PHF8 interacts with PML-RARα and functions as a transcriptional coactivator in response to all-trans retinoic acid treatment (11). Physiologically, PHF8 regulates neuronal differentiation (12) and zebrafish brain and craniofacial development (10).…”