Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Autor: Chen Ding, Mengli Zhang, Jinye Zhang, Hao Zhang, Chenxi He, Zhen Yang, Chen Yang, Dan Ye, Kun-Liang Guan, Yi-Rong Zeng, Yue Xiong, Lei Song, Cheng Zhang, Pu Wang, Yi-Ping Sun, Yu-Jie Tang, Yukun Xia, Fang Liu, Peng Liu
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Mutant
ASXL1
Biochemistry
Epigenesis
Genetic
0302 clinical medicine
Drug Discovery
FOXK1/K2
BAP1
FOXK1
Gene Expression Regulation
Leukemic
Cell Cycle
leukemia
Forkhead Transcription Factors
QP501-801
Animal biochemistry
Cell biology
Cell Transformation
Neoplastic
030220 oncology & carcinogenesis
Ubiquitin Thiolesterase
Protein Binding
Signal Transduction
Research Article
Biotechnology
STAT3 Transcription Factor
Heterozygote
Nonsense mutation
Biology
Frameshift mutation
03 medical and health sciences
Cell Line
Tumor
K2
Humans
Epigenetics
Gene
Transcription factor
Cell Proliferation
Janus Kinases
epigenetics
QH573-671
Tumor Suppressor Proteins
Cell Biology
Oxygen
Repressor Proteins
Glucose
HEK293 Cells
030104 developmental biology
Mutation
Biochemistry and Cell Biology
K562 Cells
Cytology
Zdroj: Protein & Cell, Vol 12, Iss 7, Pp 557-577 (2020)
Protein & cell, vol 12, iss 7
Protein & Cell
ISSN: 1674-8018
Popis: Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
Databáze: OpenAIRE
Externí odkaz: