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We explored the association between the serum level of cystatin C (CysC) at admission and short-term functional outcome in patients with hypertensive intracerebral hemorrhage (HICH) without chronic kidney disease (CKD). A total of 555 patients with HICH were consecutively recruited after admission and were followed-up for 3 months after admission. The primary outcome was poor functional outcome (modified Rankin Scale [mRS] score ≥ 3). The median serum CysC level in our cohort was 1.03 mg/L (interquartile range, .89-1.20). Patients were categorized into four groups according to the serum CysC quartiles. Multivariate logistic regression analysis revealed a negative association between serum CysC and poor functional outcome at 3-month follow-up (quartile [Q]1 vs. Q4: adjusted odds ratio [OR] = .260, 95% confidence interval [CI] = .098, .691, p.001). The negative association between serum CysC and poor functional outcome at 3 months was more pronounced in subgroups with smaller hematoma volume (≤ 30 mL), and absence of secondary intraventricular hemorrhage (IVH). Addition of serum CysC to a model containing conventional risk factors improved the model performance with net reclassification index (NRI) of .426% (p.001) and integrated discrimination improvement (IDI) of .043% (p.001) for poor functional outcome. Serum CysC was found to be a negative predictor of poor short-term functional outcome in HICH patients independent of renal function.

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.

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.