title: Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence.
abstract: Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) and C/EBPβ (CCAAT/enhancer-binding protein-β) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-κB pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-κB is essential for C/EBPβ upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBPβ and cooperate with C/EBPβ to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-κB to C/EBPβ during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-κB may determine the effectiveness of therapeutic drugs.
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: A-w
authors.initials: AW
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C119386:BCLAF1 protein, human; D022782:CCAAT-Enhancer-Binding Protein-beta; D016328:NF-kappa B; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin