Although histone deacetylase inhibitors (HDACis) are emerging as a new class of anticancer agents, the mechanism of tumorselective killing by HDACi is not well understood. We used suppression of mortality by antisense rescue technique (SMART) to screen the key genes responsible for the tumor-selective killing by trichostatin A (TSA). Twenty-four genes were identified, the most significant of which was ubiquitin B (UbB). The expression of UbB was selectively upregulated by TSA in tumor cells, but not non-malignant cells. Further observation indicated that TSA induced a substantial dissipation of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, and proteolytic cleavage of caspases-3/9 in HeLa cells, which was apparently mediated by ubiquitylation and the subsequent degradation of mitochondrial membrane proteins including BCL-2 and MCL-1. In contrast, knockdown of UbB expression inhibited the TSA-induced apoptotic cascade by abolishing TSA-induced ubiquitylation and the subsequent degradation of mitochondrial membrane proteins. Furthermore, apicidine, another HDACi, exhibited activity similar to that of TSA. Interestingly, TSA induced UbB-dependent proteasomal degradation of BCR-ABL fusion protein in K562 leukemic cells. Thus, our findings highlight the essential role of UbB and UbBdependent proteasomal protein degradation in HDACi-induced tumor selectivity. The mechanism provides a novel starting point for dissecting the molecular mechanism underlying the tumor selectivity of HDACi. 1-3 The clinical potential of HDACis has been well exemplified by the successful development of Vorinostat, which was recently approved by the US Food and Drug Administration for treatment of cutaneous T-cell lymphoma. 4 Despite the rapid clinical progress achieved, the mechanism of action of HDACis is not yet well understood. One of the central questions is how these agents selectively kill tumor cells while sparing normal cells. Identification of the critical intracellular targets responsible for the tumor selectivity of HDACis will further improve the design of optimized clinical protocols. More attractively, unraveling the potential 'death programs' selectively activated in tumor but not in normal cells will have broader implications for the understanding of tumorigenesis and the design of targeted therapies.Identification of the target genes essential for the selective induction of apoptosis in tumor cells has proven to be very difficult. It is well established that HDACis could affect up to 10% of all known genes at the transcriptional level. 5 In addition to HDACs, many non-histone proteins are also regulated by HDACis by influencing the molecular events of acetylation, protein-protein interactions and stability, and so on. Previously, a significant number of apoptotic and cell-cycle regulatory genes have been identified by different groups and proposed to be effectors responsible for the tumorselective action of HDACis. 6 In acute promyelocytic leukemia, however, preferential induction of tumor-n...

Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs) sensing biomechanical stimuli and subsequently releasing signals to initiate alveolar bone remodeling. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities are still unclear. This study demonstrates that the core circadian protein aryl hydrocarbon receptor nuclear translocator–like protein 1 (BMAL1) in PDLCs is highly involved in sensing and delivering biomechanical signals. Orthodontic force upregulates BMAL1 expression in periodontal tissues and cultured PDLCs in manners dependent on ERK (extracellular signal–regulated kinase) and AP1 (activator protein 1). Increased BMAL1 expression can enhance secretion of CCL2 (C-C motif chemokine 2) and RANKL (receptor activator of nuclear factor–κB ligand) in PDLCs, which subsequently promotes the recruitment of monocytes that differentiate into osteoclasts. The mechanistic delineation clarifies that AP1 induced by orthodontic force can directly interact with the BMAL1 promoter and activate gene transcription in PDLCs. Localized administration of the ERK phosphorylation inhibitor U0126 or the BMAL1 inhibitor GSK4112 suppressed ERK/AP1/BMAL1 signaling. These treatments dramatically reduced osteoclastic activity in the compression side of a rat orthodontic model, and the OTM rate was almost nonexistent. In summary, our results suggest that force-induced expression of BMAL1 in PDLCs is closely involved in controlling osteoclastic activities during OTM and plays a vital role in alveolar bone remodeling. It could be a useful therapeutic target for accelerating the OTM rate and controlling pathologic bone-remodeling activities.