Bclaf1 is an important NF-kappa B signaling transducer and C/EBP beta regulator in DNA damage-induced senescence

摘要

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-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) and C/EBP beta (CCAAT/enhancer-binding protein-beta) 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-kappa B pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-kappa B is essential for C/EBP beta upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBP beta and cooperate with C/EBP beta 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-kappa B to C/EBP beta 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-kappa B may determine the effectiveness of therapeutic drugs.