The Role of Additional Sex Combs-Like Proteins in Cancer

Abstract

Additional sex combs-like (ASXL) proteins are mammalian homologs of Addition of sex combs (Asx), a protein that regulates the balance of trithorax and Polycomb function in Drosophila. All three ASXL family members (ASXL1, ASXL2, and ASXL3) are affected by somatic or de novo germline mutations in cancer or rare developmental syndromes, respectively. Although Asx is characterized as a catalytic partner for the deubiquitinase Calypso (or BAP1), there are domains of ASXL proteins that are distinct from Asx and the roles and redundancies of ASXL members are not yet well understood. Moreover, it is not yet fully clarified if commonly encountered ASXL1 mutations result in a loss of protein or stable expression of a truncated protein with dominant-negative or gain-of-function properties. This review summarizes our current knowledge of the biological and functional roles of ASXL members in development, cancer, and transcription.

Figure 1.

Timeline of discovery of Additional sex combs-like family members and characterization of their effects on the epigenome, development, and cancer.

Figure 2.

Known and proposed biochemical and epigenomic functions associated with Additional sex combs-like (ASXL) family members. ASXL1 and ASXL2 have been copurified with BAP1 in numerous reports and serve as a deubiquitinase for histone H2A lysine 119 with BAP1 termed the Polycomb repressive deubiquitinase (PR-DUB). At least one report has suggested that ASXL1 and ASXL2 form mutually exclusive complexes with BAP1 in the PR-DUB. In addition, HCF1, OGT, and KDM1B all appear to be in complex with BAP1 as well. Whether the association of KDM1B with BAP1 has any influence on histone H3 lysine 4 mono- or dimethylation (H3K4me1/2) is currently unclear. In addition, to opposing the function of the Polycomb repressive complex 1 (PRC1)-mediated H2AK119 ubiquitination, ASXL1 loss has also been repeatedly associated with global loss of histone H3 lysine 27 trimethylation (H3K27me3). Whether the H3K27me3 loss associated with ASXL1 loss is secondary to loss of H2AK119Ub and/or because of impaired Polycomb repressive complex 2 (PRC2) remains to be further clarified. Finally, ASXL1 and ASXL2 have been proposed to physically interact and/or functionally affect the function of a number of nuclear hormone receptors (NHRs) including PPARγ and the estrogen and androgen receptors (ER and AR, respectively).

Figure 3.

Protein domain structure and location of amino acids affected by mutations in ASXL1, ASXL2, and ASXL3. Only nonsense or frameshift mutations are shown for each protein here. Mutations shown in black triangles are previously reported as germline mutations in Bohring–Opitz syndrome (ASXL1) or Bohring–Opitz-like syndrome (ASXL3), whereas mutations in red, blue, or green triangles have been reported as somatic mutations in ASXL1, ASXL2, or ASXL3, respectively. For ASXL1, only somatic mutations that have been described in more than one patient or as a germline mutation are shown.

Figure 4.

Histogram of somatic mutational frequency of (A) ASXL1, (B) ASXL2, and (C) ASXL3 in cancer, as well as in (D) clonal hematopoiesis of indeterminate potential. AA, Aplastic anemia; AML, acute myeloid leukemia; ccRCC, clear cell renal cell carcinoma; CMML, chronic myelomonocytic leukemia; CLL, chronic lymphocytic leukemia; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; MDS, myelodysplastic syndromes; PMF, primary myelofibrosis; sAML, secondary AML.