The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes.

HACE1 is a HECT family E3 ubiquitin-protein ligase with broad but incompletely understood tumor suppressor activity. Here, we report a previously unrecognized link between HACE1 and signaling complexes containing mammalian target of rapamycin (mTOR). HACE1 blocks mTORC1 and mTORC2 activities by reducing mTOR stability in an E3 ligase-dependent manner.

Surface and Global Proteome Analyses Identify ENPP1 and Other Surface Proteins as Actionable Immunotherapeutic Targets in Ewing Sarcoma.

Purpose: Ewing sarcoma is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. Although the survival rate of patients diagnosed with localized disease is approximately 70%, this decreases to approximately 30% for patients with metastatic disease and only approximately 10% for treatment-refractory disease, which have not changed for decades.

De novo and cell line models of human mammary cell transformation reveal an essential role for Yb-1 in multiple stages of human breast cancer.

Breast cancer heterogeneity has made it challenging to identify mechanisms critical to the initial stages of their genesis in vivo. Here, we sought to interrogate the role of YB-1 in newly arising human breast cancers as well as in established cell lines. In a first series of experiments, we found that short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonising activity in immunodeficient mice.

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis.

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner.

Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated.

Valorizing lignin-like dyes and textile dyeing wastewater by a newly constructed lipid-producing and lignin modifying oleaginous yeast consortium valued for biodiesel and bioremediation.

Construction of a multipurpose yeast consortium suitable for lipid production, textile dye/effluent removal and lignin valorization is critical for both biorefinery and bioremediation. Therefore, a novel oleaginous consortium, designated as OYC-Y.BC.

Enhancement of biodiesel yield from a halophilic green microalga isolated under extreme hypersaline conditions through stepwise salinity adaptation strategy.

In the present study, a halophilic microalgal species was isolated from a hypersaline lagoon with salinity average of 45.3‰ and identified as Dunaliella salina KSA-HS022. It was further cultivated at a salinity range of 50-250‰, applied directly to batch cultures or through stepwise increase in a semi-continuous culture.

HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases.

HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that is frequently mutated in human lung cancer.

Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis.

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS-275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells.

Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma.

Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations.

Pharmacological systems analysis defines EIF4A3 functions in cell-cycle and RNA stress granule formation.

The RNA helicase EIF4A3 regulates the exon junction complex and nonsense-mediated mRNA decay functions in RNA transcript processing. However, a transcriptome-wide network definition of these functions has been lacking, in part due to the lack of suitable pharmacological inhibitors. Here we employ short-duration graded EIF4A3 inhibition using small molecule allosteric inhibitors to define the transcriptome-wide dependencies of EIF4A3.

HACE1 is a potential tumor suppressor in osteosarcoma.

Osteosarcoma is a malignant bone sarcoma characterized by extensive genomic disruption and a propensity for metastatic spread. Osteoid production suggests a close relationship with normal osteoblasts, and the latter are the presumptive cell of origin of this disease. The HACE1 gene, localized to human chromosome 6q21, encodes the HACE1 HECT E3 ligase, a tumor suppressor in diverse tumors that acts in part by targeting the activated form of RAC1 GTPase for proteasomal degradation.

Translational control of aberrant stress responses as a hallmark of cancer.

Altered mRNA translational control is emerging as a critical factor in cancer development and progression. Targeting specific elements of the translational machinery, such as mTORC1 or eIF4E, is emerging as a new strategy for innovative cancer therapy. While translation of most mRNAs takes place through cap-dependent mechanisms, a sub-population of cellular mRNA species, particularly stress-inducible mRNAs with highly structured 5'-UTR regions, are primarily translated through cap-independent mechanisms.

Potential of macroalgae for biodiesel production: Screening and evaluation studies.

Nowadays, biofuel production is a fast expanding industry and is facing a growing dilemma about a feedstock source capable of keeping up with demand. Recently, macroalgae have been attracting a wide attention as a source for biofuel. In the present study, ten macroalgae were collected and screened as biodiesel feedstocks.

MYCN amplified neuroblastoma requires the mRNA translation regulator eEF2 kinase to adapt to nutrient deprivation.

MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN amplification in childhood neuroblastoma (NB) is associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors.

An Aqueous Extract of Marine Microalgae Exhibits Antimetastatic Activity through Preferential Killing of Suspended Cancer Cells and Anticolony Forming Activity.

Research on marine natural products as potential anticancer agents is still limited. In the present study, an aqueous extract of a Canadian marine microalgal preparation was assessed for anticancer activities using various assays and cell lines of human cancers, including lung, prostate, stomach, breast, and pancreatic cancers, as well as an osteosarcoma. In vitro, the microalgal extract exhibited marked anticolony forming activity.

Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility.

Unlabelled: Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways.

Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis.

Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas.

YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1.

Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown.

The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation.

Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis.

ERBB4 confers metastatic capacity in Ewing sarcoma.

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro.

Expression and stability of hypoxia inducible factor 1α in osteosarcoma.

Background: Hypoxia contributes to both physiological and pathological processes and its effects are mainly mediated through the transcription factors hypoxia-inducible factor 1α and 2α (HIF1α and HIF2α). The purpose of this study was to examine the role of these proteins in osteosarcoma progression.

Procedures: We developed a method to isolate primary human osteoblast cell lines.

Differential effects of Co(2+) and Ni(2+) on protein metabolism in Scenedesmus obliquus and Nitzschia perminuta.

Growth, morphological changes, amino acid composition, total soluble protein, and protein electrophoretic pattern were monitored for Scenedesmus obliquus and Nitzschia perminuta grown in the presence of different concentrations of Co(2+) and Ni(2+). Lower concentrations of cobalt stimulated the dry mass production and total soluble protein content of the two algae, whereas higher concentrations were inhibitory. Generally, N.