Functional and cancer genomics of ASXL family members

Abstract

Additional sex combs-like (ASXL)1, ASXL2 and ASXL3 are human homologues of the Drosophila Asx gene that are involved in the regulation or recruitment of the Polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex. ASXL proteins consist of ASXN, ASXH, ASXM1, ASXM2 and PHD domains. ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor. ASXL family members are epigenetic scaffolding proteins that assemble epigenetic regulators and transcription factors to specific genomic loci with histone modifications. ASXL1 is involved in transcriptional repression through an interaction with PRC2 and also contributes to transcriptional regulation through interactions with BAP1 and/or NHR complexes. Germ-line mutations of human ASXL1 and ASXL3 occur in Bohring-Opitz and related syndromes. Amplification and overexpression of ASXL1 occur in cervical cancer. Truncation mutations of ASXL1 occur in colorectal cancers with microsatellite instability (MSI), malignant myeloid diseases, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, and liver, prostate and breast cancers; those of ASXL2 occur in prostate cancer, pancreatic cancer and breast cancer and those of ASXL3 are observed in melanoma. EPC1-ASXL2 gene fusion occurs in adult T-cell leukaemia/lymphoma. The prognosis of myeloid malignancies with misregulating truncation mutations of ASXL1 is poor. ASXL family members are assumed to be tumour suppressive or oncogenic in a context-dependent manner.

Figure 1

The ASXL family.(A) Chronology of the ASXL family. Cumulative publication numbers of ASXL1, ASXL2 or ASXL3 manuscripts in the PubMed database are shown by open bars, whereas those of ASXL1 mutations in malignant myeloid diseases are depicted with closed bars. (B) Phylogeny of the vertebrate ASXL family members. Hs, human; Gg, chicken; Mm, mouse. (C) Conserved domain architecture of the ASXL family members, consisting of the ASXN, ASXH, ASXM1, ASXM2 and PHD domains. The LVxxLL motif in the ASXM2 domain and the C4HC3 motif in the PHD domain are shown above the amino-acid alignment. The conserved amino acids are shown by asterisks below the alignment.

Figure 2

The ASXL network.(A) ASXL1-binding partners. The ASXN and PHD domains are binding modules for DNA or modified histones. The regions around the ASXH, ASXM1 and ASXM2 domains are binding modules for BAP1, KDM1A (LSD1), NCOA1 and NHRs, such as retinoic acid receptors and oestrogen receptor. CBX5 * indicates CBX5 binds to ASXL1, but not to ASXL2. Truncation mutations, clustered within the MCR region, give rise to aberrant ASXL proteins with ASXN and ASXH domains. (B) Involvement of the ASXL proteins in transcriptional regulation. ASXL proteins assemble BAP1, KDM1A, NCOA1 and NHRs to specific genomic loci with histone modification. ASXL proteins recruit BAP1 and NHR complexes for transcriptional activation, as well as PRC for transcriptional repression. The ASXL proteins activate or repress transcription of the target genes in a context-dependent manner.