DAXX in cancer: phenomena, processes, mechanisms and regulation

Abstract

DAXX displays complex biological functions. Remarkably, DAXX overexpression is a common feature in diverse cancers, which correlates with tumorigenesis, disease progression and treatment resistance. Structurally, DAXX is modular with an N-terminal helical bundle, a docking site for many DAXX interactors (e.g. p53 and ATRX). DAXX's central region folds with the H3.3/H4 dimer, providing a H3.3-specific chaperoning function. DAXX has two functionally critical SUMO-interacting motifs. These modules are connected by disordered regions. DAXX's structural features provide a framework for deciphering how DAXX mechanistically imparts its functions and how its activity is regulated. DAXX modulates transcription through binding to transcription factors, epigenetic modifiers, and chromatin remodelers. DAXX's localization in the PML nuclear bodies also plays roles in transcriptional regulation. DAXX-regulated genes are likely important effectors of its biological functions. Deposition of H3.3 and its interactions with epigenetic modifiers are likely key events for DAXX to regulate transcription, DNA repair, and viral infection. Interactions between DAXX and its partners directly impact apoptosis and cell signaling. DAXX's activity is regulated by posttranslational modifications and ubiquitin-dependent degradation. Notably, the tumor suppressor SPOP promotes DAXX degradation in phase-separated droplets. We summarize here our current understanding of DAXX's complex functions with a focus on how it promotes oncogenesis.

Figure 1.

DAXX structure and interacting proteins. The modular structure arrangement of DAXX is depicted. SIM: SUMO-interacting motif, 4HB: DAXX helix bundle, HBD: histone-binding domain, NLS: nuclear localization signal. Proteins that are known to interact with specific regions of DAXX are shown. The 4HB is probably the major binding site for proteins that interact with the DAXX N-terminal region, while SIM2 likely plays a major role in binding proteins that interact with the DAXX C-terminal region. The lines below or above each protein group are not meant to be precise. Readers are referred to the original publications reporting a specific interaction (see Table 1).

Figure 2.

DAXX mRNA expression in cancer. (A) Boxplots depicting DAXX mRNA expression levels across multiple cancer types along with corresponding normal controls (data from the TCGA portal or other published datasets of clinical cancer samples as indicated). (B) DAXX mRNA levels are further elevated in metastases compared to primary tumors. BCa: breast cancer, mBCa: metastatic breast cancer, PCa: prostate cancer, mPCa: metastatic prostate cancer, CCa: colon cancer, mCCa: metastatic colon cancer.

Figure 3.

DAXX in cell death. Several ways in which apoptosis is induced by DAXX are shown. Induction of cell death by interacting with the death domain of Fas and other associated proteins, resulting in the activation of ASK1–JNK cell death signaling (A and B), and by TGFβ signaling, which mediates non-SMAD pathway activation (C). AKT1 blocks a cell death pathway mediated by DAXX through a negative-feedback loop (D). During necrosis in retinal ganglion cells, RIPK3 interacts with and phosphorylates DAXX (E). In the nucleus, DAXX-mediated cell death appears to be mediated by the PML-NBs, presumably by interacting with other proteins within PML-NBs (F). In the nucleus, DAXX can repress the expression of anti-apoptotic genes such as Survivin (BBC3) (G). DAXX activates the ASK1–JNK cascade in the nucleus upon UV exposure (H). DAXX can activate proapoptotic genes, for example, via p53 activation (I). In this case, the localization of DAXX and AXIN in PML-NBs may be important. DAXX seems to potentiate UV-induced apoptosis through modulating the SUMO E3 ligase PIAS1 activity (J). In general, cytoplasmic localization of DAXX has been described as a proapoptotic event, which can be induced by cellular proteins, viral infection and metabolites (e.g., 4-HNE), and blocked by cytoprotective factors (K). DAXX represses the expression of several components of autophagy machinery such as ULK1, DAPK1 and DAPK3, ultimately suppressing autophagic cell death (L). Cellular stresses such as the presence of interferons (IFNs), UV irradiation, and oxidative stress can trigger DAXX-mediated cell death events originated from cell surface receptors or regulation of gene expression in the nucleus.

Figure 4.

Mechanisms underlying DAXX-mediated transcriptional regulation. (A) DAXX, as an H3.3 chaperone along with ATRX, is recruited to chromatin by interacting with a TF. This complex deposits H3.3 to specific chromatin sites. Histone methyltransferases (KMTs) such as SETDB1 and SUV39H1 are associated with the DAXX repression complexes and mediate H3K9 trimethylation to repress transcription. (B) DAXX interacts with HDAC1, HDAC2 and HDAC3 as well as DNMT1 to repress transcription. KMTs such as SETDB1 are associated with the DAXX-HDAC1 repression complex. (C) DAXX can activate transcription through interacting with a TF, and possibly also with coactivator(s) such as CBP. H3.3 deposition may also be involved in DAXX-mediated gene activation. Multivalent interactions, partly mediated by the two SIMs of DAXX, are probably important for DAXX-mediated transcriptional repression and activation (not depicted).