SUMOylated MAFB promotes colorectal cancer tumorigenesis.
The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment.
State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Lin-Sen
LS
Yang
Department of General Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xiao-Jian
XJ
Zhang
State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Yin-Yin
YY
Xie
State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xiao-Jian
XJ
Sun
Department of General Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Ren
R
Zhao
State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Qiu-Hua
QH
Huang
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019295:Computational Biology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D058207:Sumoylation; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
C490407:MAFB protein, human; D051258:MafB Transcription Factor; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
CDK6; MAFB; SUMOylation; cell cycle; colorectal cancer