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Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics. [Display omitted] • CRISPR screening identifies PRMT1 as a crucial promoter of ferroptosis • PRMT1 transcriptionally represses SLC7A11 expression • PRMT1 posttranslationally inhibits the enzymatic activity of FSP1 • Inhibition or depletion of PRMT1 protects ConA-induced ferroptotic liver damage Zhang et al. show that, as a pro-ferroptotic gene, PRMT1 not only inhibits SLC7A11 expression to reduce GSH abundance but also suppresses the membrane localization and enzymatic activity of FSP1 through arginine dimethylation to decrease CoQ10H2 content. They provide a rationale for inhibiting PRMT1 in the treatment of ferroptosis-related diseases. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer. [Display omitted] • YAP/TEAD inhibits NLRC5 transcription to dampen MHC class I neoantigen presentation • The NuRD complex is required for the YAP/TEAD-repressed expression of MHC class I APP genes • Inhibition or depletion of YAP improves antitumor immunity through NLRC5-MHC class I axis Peng et al. show that the YAP/TEAD complex cooperates with the NuRD complex to repress NLRC5 transcription, thus impairing the MHC class I APP pathway and CD8+ CTL-mediated killing of cancer cells. They provide a rationale for inhibiting YAP activity in immunotherapy for cancer. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in oncogenesis of various human malignancies. It has been demonstrated that there is a direct interaction between β-catenin and PPARγ. Here we examined the effects of fifteen reported PPAR ligands in a reporter gene assay that is dependent on β-catenin activation of TCF/LEF transcription factors; only the thiazolidinedione PPARγ agonists troglitazone, rosiglitazone and pioglitazone, and a non-thiazolidinedione PPARγ activator GW1929 inhibited β-catenin-induced transcription in a PPARγ dependent fashion. The results from mammalian one-hybrid experiments showed that functional PPARγ was necessary for ligand-dependent inhibition of β-catenin transactivation. However, a PPARγ activator Fmoc-Leu could not repress β-catenin-mediated signaling and its transactivation activity. These results indicate that activation of PPARγ is necessary, but not sufficient, for the β-catenin antagonistic activity of a PPARγ agonist, and that the inhibitory compounds interfere directly with β-catenin transactivation activity. [Copyright &y& Elsevier]

Abstract: A series of amides of ethacrynic acid was prepared and evaluated for their ability to inhibit Wnt signaling and decrease the survival of CLL cells. Several of the most potent derivatives were active in the low micromolar range. Reduction of the α,β-unsaturated carbon–carbon double bond of EA abrogated both the inhibition of Wnt signaling as well as the decrease in CLL survival. Preliminary mechanism of action studies suggest that these derivatives covalently modify sulfhydryl groups present on transcription factors important for Wnt/β-catenin signaling. [Copyright &y& Elsevier]

Abstract: We recently confirmed that ciclopirox olamine inhibits Wnt/beta catenin signalling in myeloma. Griseofulvin (GF) has similar chemical features as compared to ciclopirox olamine. In this study the anti-tumor effect of GF was investigated. GF demonstrated a major apoptotic activity in various human and murine myeloma and lymphoma cell lines as well as in human primary cells. In vivo, tumor growth as well as overall survival were significantly reduced in mice treated with GF as compared to untreated mice. In conclusion, our results reveal a significant selective induction of apoptosis by GF and suggest a significant in vivo effect against myeloma. [Copyright &y& Elsevier]

R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARγ pathway. PPARγ protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARγ function. Negative regulation of PPARγ was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARγ protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARγ pathways, ultimately leading to negative regulation of PPARγ activity and tumor growth inhibition. [Copyright &y& Elsevier]

Abstract: It was recently confirmed that the diuretic agent ethacrynic acid (EA) inhibits Wnt/beta catenin signaling in myeloma. This study investigated the antitumor effect of EA in vivo in a murine myeloma model. In vivo, tumor growth was significantly reduced and overall survival significantly prolonged in mice treated with EA as compared to untreated mice. Interestingly, this effect was higher as compared to the effect by lenalidomide, a commonly used drug against myeloma. These results reveal a significant in vivo effect by EA against myeloma. [Copyright &y& Elsevier]

Wnt/β-catenin signaling cascade is highly associated with tumorigenesis and progression of various cancers. Targeting Wnt/β-catenin signaling exhibits a promising way for cancer treatment. Herein, dual-stimuli responsive nanotheranostics was synthesized, which was composed of melanin coated magnetic nanoparticles (MMNs) and Wnt signaling inhibitor obatoclax (OBX) for multimodality imaging guided mild hyperthermia-enhanced chemotherapy. The MMNs could be used as contrast agents for magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) guided photothermal therapy. In addition, OBX-loaded MMNs (OBX-MMNs) were specific response to both pH changes and near-infrared (NIR) light illumination, which could trigger OBX release. Most intriguingly, tumor tissue accumulation and cellular internalization of this nanotheranostics could be dramatically enhanced through mild hyperthermia generated by laser-irradiated MMNs. Laser irradiation exhibited efficient chemotherapeutic outcome through enhancing OBX-mediated inhibition of the Wnt/β-catenin signaling. Our results indicated the as-prepared OBX-MMNs hold great potential for MR/PA dual-modal imaging guided mild hyperthermia-enhanced chemotherapy. [ABSTRACT FROM AUTHOR]