Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.

Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

Background: The optimal design concept and the safety of drug-coated balloons (DCBs) have not been completely determined yet. Also, the optimal approach for DCB-based revascularization of peripheral artery diseases still remains undefined. This study was designed to explore the in vivo pharmacokinetic and histopathological effects of DCBs using Ranger and 4 Chinese DCBs after implantation and administration in New Zealand rabbits. Materials and Methods: Fifty New Zealand rabbits were divided into 5 groups with 10 rabbits in each group according to the DCB used: Ranger (Boston Scientific), Orchid (Acotec), Reewarm (Endovastec), Ultrafree (Zylox), and Yaohang (Polyrey). After being guided to the lower segment of the abdominal aorta, the DCB was inflated for 3 minutes. Plasma, inflated infrarenal aorta, vastus lateralis muscle, anterior tibial muscle, and right toes were harvested for histological and paclitaxel concentration analyses 4 hours or 28 days after the angioplasty. Results: At 4 hours after aortic angioplasty, the overall paclitaxel concentrations in aortic wall were not statistically different (p = 0.050), but the paclitaxel concentrations in vastus lateralis muscle (p = 0.002), anterior tibial muscle (p = 0.006) and toe (p < 0.001) were not totally same according to the results of Kruskal-Wallis test. In toe, concentrations of paclitaxel were significantly lower for the Ranger (120.8 ng/g) DCB than for the Orchid (1880 ng/g; p = 0.008), Reewarm (347 ng/g; p = 0.016), and Ultrafree (261 ng/g; p = 0.016) DCBs. Concentrations of paclitaxel in the toe were not statistically different between Ranger and Yaohang DCBs (p = 0.421). Neointimal area (p < 0.001), neointimal thickness (p < 0.001), and percentage of luminal stenosis (p < 0.001) were less for Ranger DCB than for other DCBs 28 days after aortic angioplasty. The differences in paclitaxel concentrations in tissues 28 days after aortic angioplasty were not statistically significant. Conclusion: Different design concepts will make a difference in the in vivo pharmacokinetic and histopathological effects of DCBs. The Ranger DCB can achieve similar drug delivery efficiency as other higher-dose DCBs and fewer neointimal hyperplasia. Although clinical implications remain to be further investigated, the present results may provide implications for the design and use of DCBs. Clinical Impact: The current preclinical study suggested that different design concepts would make a difference in the pharmacokinetic and histopathological effects of drug-coated balloons (DCBs). Though Ranger DCB had the lowest paclitaxel loading in this study, it still achieved similar drug delivery efficiency with other higher-dose DCBs. Also, neointimal hyperplasia was less for the Ranger DCB than for the other DCBs 28 days after aortic angioplasty. Although clinical implications remain to be further investigated, the present results may provide implications for the design and use of DCBs.