Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent-Myc-switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for Myc-dependent tumor growth, and patient survival significantly correlates with SAE1/SAE2 levels in Myc-high tumors. These studies reveal a mitotic vulnerability of Myc-driven cancers, demonstrate that inhibiting sumoylation impairs Myc-dependent tumorigenesis, and suggest inhibiting SUMOylation may have therapeutic benefits for patients with Myc-driven cancer.

Pleiotrophin (PTN) plays diverse roles in cell growth and differentiation. In this investigation, we demonstrate that PTN plays a negative role in adipogensis and that glycogen synthase kinase 3b (GSK-3b) and b-catenin are involved in the regulation of PTN-mediated preadipocyte differentiation. Knocking down the expression of PTN using siRNA resulted in an increase in phospho-GSK-3b expression, and the accumulation of nuclear b-catenin, which are critical downstream signaling proteins for both the PTN and Wnt signaling pathways. Our investigation suggests that there is a PTN/PI3K/AKT/GSK-3b/b-catenin signaling pathway, which cross-talks with the Wnt/Fz/GSK-3b/bcatenin pathway and negatively regulates adipogenesis.

BackgroundBaicalin is a flavonoid derived from Scutellaria baicalensis, used in Chinese herbal medicine. Activation of the sirtuin 1 gene (SIRT1) and adenosine monophosphate (AMP)-activated protein kinase gene (AMPK), the SIRT1/AMPK signaling pathway, is associated with human malignant tumors. The aim of this study was to investigate the effects of baicalin on the cell viability, apoptosis, proliferation, and migration of human non-small cell lung cancer (NSCLC) cells, A549 and H1299, in vitro.Material/MethodsHuman NSCLC cells, A549 and H1299, were treated with serial doses of baicalin. Small interfering RNA (siRNA) silencing of the SIRT1 and AMPK genes was performed using cell transfection. The MTT assay was used to determine cell viability, flow cytometry was used to measure cell apoptosis, wound healing and transwell assays were used to assess cell migration of A549 and H1299 cells. Western blotting was used to measure protein expression and phosphorylation levels in untreated A549 and H1299 cells, and cells treated with increasing doses of baicalin.ResultsBaicalin inhibited the viability, migration, and invasion of A549 and H1299 cells, and increased cell apoptosis in a dose-dependent manner. Baicalin activated the SIRT1/AMPK and mechanistic target of rapamycin (mTOR), and SIRT1/AMPK and matrix metalloproteinase (MMP) signaling in A549 and H1299 cells in a dose-dependent manner. siRNA silencing of SIRT1 and AMPK reduced the effects of baicalin on cell proliferation and migration.ConclusionsBaicalin, a flavonoid used in Chinese herbal medicine, inhibited the proliferation and migration of human NSCLC cells, A549 and H1299, by activating the SIRT1/AMPK signaling pathway.

The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.he Ras family of small GTPases are signal transduction molecules downstream of growth factor receptors. Ras activates a number of downstream effector pathways to regulate cell proliferation, survival and motility, these effectors include the MAP kinase (MAPK) pathway, the PI3-kinase (PI3K) pathway, the small GTPases RalA, RalB, and Rho, and phospholipase-Ce (1). Activating mutations in Ras are frequently found in human malignancies, with mutations in the KRAS gene being particularly prevalent. KRAS mutations occur in ∼60% of pancreatic ductal carcinomas, 26% of lung adenocarcinomas, and 45% of colorectal carcinomas, as well as a significant fraction of ovarian, endometrial, and biliary track cancers (2, 3). A salient hallmark of the Ras oncogene is its ability to transform cells to enable anchorage-independent 3D colony growth in vitro and tumor growth in vivo. Consequently, Ras mutant cancer cells often exhibit oncogene addiction to Ras such that extinction of the Ras oncogene leads to either a reversion of the transformed phenotype or loss of viability (4, 5). Therapeutically, the Ras oncoprotein has proven pharmacologically intractable thus far: intensive drug screening efforts have not yielded high-affinity, selective Ras inhibitors. Farnesyltransferase inhibitors that aimed to block Ras membrane localization are ineffective against KRAS because of its alternative geranylgeranylation. Inhibitors targeting Ras effector kinases, including MEK, PI3K, and Akt, are currently undergoing clinical evaluations, but they have yet to demonstrate clear clinical benefits (6). Thus, KRAS mutant tumors represent a class of "recalcitrant cancer" with urgent, unmet therapeutic needs.To gain new insight into the genetic dependencies of Ras mutant cancers and discover new therapeutic targets, we and others have previously carried out genome-wide synthetic lethal screens in KRAS mutant and WT cells to identify genes whose depletion leads to greater toxicity in KRAS mutant cells. In our screen we found a wide array of genes, many of which are involved in cellular stress response, that are required to maintain the viability of KRAS mutant cells (7). We proposed the concept of "nononcogene addiction" to explain the heig...