Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer.

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.

Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host-microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow-up cohort, where 22 subjects with varying degree of HS are characterized.

Role of Tissue Transglutaminase Catalytic and Guanosine Triphosphate-Binding Domains in Renal Cell Carcinoma Progression.

Tissue transglutaminase (TG2) is a multifunctional protein that can act as a cross-linking enzyme, GTPase/ATPase, protein kinase, and protein disulfide isomerase. TG2 is involved in cell adhesion, migration, invasion, and growth, as well as epithelial-mesenchymal transition (EMT). Our previous findings indicate that the increased expression of TG2 in renal cell carcinoma (RCC) results in tumor metastasis with a significant decrease in disease- and cancer-specific survival outcome. Given the importance of the prometastatic activity of TG2 in RCC, in the present study, we aim to investigate the relative contribution of TG2's transamidase and guanosine triphosphate (GTP)-binding/GTPase activity in the cell migration, invasion, EMT, and cancer stemness of RCC. For this purpose, the mouse RCC cell line RenCa was transduced with wild-type-TG2 (wt-TG2), GTP-binding deficient-form TG2-R580A, transamidase-deficient form with low GTP-binding affinity TG2-C277S, and transamidase-inactive form TG2-W241A. Our results suggested that predominantly, GTP-binding activity of TG2 is responsible for cell migration and invasion. In addition, CD marker analysis and spheroid assay confirmed that GTP binding/GTPase activity of TG2 is important in the maintenance of mesenchymal character and the cancer stem cell profile. These findings support a prometastatic role for TG2 in RCC that is dependent on the GTP binding/GTPase activity of the enzyme.

Advances in the epigenetics of fibroblast biology and fibrotic diseases.

Fibroblasts have a central role in tissue fibrosis and fibrotic diseases. Fibroblast activation is regulated by several mechanisms including epigenetic modifications; histone modifications, DNA methylation and non-coding RNAs. Although research has significantly contributed to our basic understanding of fibrotic diseases over the last decade, cooperative activity of epigenetic mechanisms demonstrates the complexity of fibrogenesis. This review will summarise the latest epigenetic advances in fibroproliferative diseases. Current studies investigating biological implications of epigenetic modifiers, inhibitors of DNA methylation/histone modifying enzymes are promising. Given that ncRNA-based or CRISPR-based epigenetic-editing have shown therapeutic potential in the preclinical models; we consider epigenetic mechanisms represent a potential tool with clinical utility.

Transglutaminase 2: The Maestro of the Oncogenic Mediators in Renal Cell Carcinoma.

Transglutaminase 2 (TG2) is a multifunctional crosslinking enzyme that displays transamidation, protein disulfide isomerase, protein kinase, as well as GTPase and ATPase activities. TG2 can also act as an adhesion molecule involved in the syndecan and integrin receptor signaling. In recent years, TG2 was implicated in cancer progression, survival, invasion, migration, and stemness of many cancer types, including renal cell carcinoma (RCC). Von Hippel-Lindau mutations leading to the subsequent activation of Hypoxia Inducible Factor (HIF)-1-mediated signaling pathways, survival signaling via the PI3K/Akt pathway resulting in Epithelial Mesenchymal Transition (EMT) metastasis and angiogenesis are the main factors in RCC progression. A number of studies have shown that TG2 was important in HIF-1- and PI3K-mediated signaling, VHL and p53 stabilization, glycolytic metabolism and migratory phenotype in RCC. This review focuses on the role of TG2 in the regulation of molecular pathways nurturing not only the development and propagation of RCC, but also drug-resistance and metastatic potential.