FBXO43 promotes cell cycle progression in cancer cells through stabilizing SKP2.

FBXO43 is a member of the FBXO subfamily of F-box proteins, known to be a regulatory hub during meiosis. A body of data showed that FBXO43 is overexpressed in a number of human cancers. However, whether and how FBXO43 affects cell cycle progression and growth of cancer cells remain elusive. In this study, we provide first piece of evidence, showing a pivotal role of FBXO43 in cell cycle progression and growth of cancer cells. Specifically, FBXO43 acts as a positive cell cycle regulator with an oncogenic activity in variety types of human cancer, including non-small cell lung cancer, hepatocellular carcinoma and sarcoma. Mechanistically, FBXO43 interacts with phosphorylated SKP2 induced by AKT1, leading to reduced SKP2 auto-ubiquitylation and subsequent proteasome degradation. Taken together, our study demonstrates that FBXO43 promotes cell cycle progression by stabilizing SKP2, and FBXO43 could serve as a potential anti-cancer target.

The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis.

Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene's transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2's protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.

FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation.

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.

The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11ß-HSD1.

Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue-specific level, glucocorticoid signal is controlled by 11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1). Up-regulation of 11ß-HSD1 expression during non-alcoholic fatty liver disease (NAFLD) has been previously shown, while 11ß-HSD1 inhibition has been shown to reduce hepatic lipids in NAFLD, but the underlying mechanisms remain unclear. Here, in this study, we created in vitro cell culture and in vivo transgenic hepatocyte-specific 11ß-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 11ß-HSD1 during lipid metabolism dysfunction. We found that 11ß-HSD1 overexpression activated glucocorticoid receptors and promoted their nuclear translocation, and then stimulating gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and ACC1. Our results suggested that overexpression of 11ß-HSD1 induced lipid accumulation, at least partially through the GR/gp78/Insig2/SREBP1 pathway, which may serve as a potential diagnostic and therapeutic target for treatment of NAFLD.

Bruceine A protects against diabetic kidney disease via inhibiting galectin-1.

Bruceine A is a natural quassinoid compound extracted from the fruit of the Traditional Chinese Medicine Brucea javanica (L.) Merr. that has various types of various biological activities. However, whether the compound has a protective effect on diabetic kidney disease remains unknown. Galectin-1 is actively involved in a variety of chronic inflammation-relevant human diseases including diabetic kidney disease. Here, we identified Bruceine A as a kidney protective molecule against a model of diabetic kidney disease in db/db mice with potent anti-inflammatory activity both in vitro and in vivo. Mechanistically, by selectively binding to the conserved carbohydrate-recognition domain of galectin-1 and disrupting the interaction between galectin-1 and the receptor for activated protein C kinase 1, Bruceine A was found to inhibit galectin-1-mediated inflammatory signal transduction under high glucose stress in rat mesangial HBZY-1 cells. Thus, our findings reveal Bruceine A as an unidentified galectin-1 inhibitor affording significant protection against diabetic kidney disease and may provide novel pharmacological therapeutics for the disease.

miR-23a/b-3p promotes hepatic lipid accumulation by regulating Srebp-1c and Fas.

miR-23a-3p and miR-23b-3p are members of the miR-23~27~24-2 superfamily. The role of miR-23a/b-3p in regulating hepatic lipid accumulation is still unknown. Here, we found that increased miR-23a-3p and miR-23b-3p levels were accompanied by an increase in the protein levels of the sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) in the steatotic livers of mice fed a high-fat diet and leptin receptor-deficient type 2 diabetic mice (db/db). Importantly, overexpression of miR-23a/b-3p in Hep1-6 cells elevated the intracellular triglyceride level and upregulated the expression of Srebp-1c and Fas. Taken together, these results suggested that miR-23a/b-3p enhanced mRNA stability by binding the 5'-UTR of Srebp-1c and Fas mRNA, thereby promoting triglyceride accumulation in hepatocytes.