摘要：Cancer cells undergo metabolic adaption to sustain their survival and growth under metabolic stress conditions, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs contribute to this metabolic adaption of cancer cells. Here we show that linc01564 is induced in response to glucose deprivation by the transcription factor ATF4. Linc01564 functions to facilitate hepatocellular carcinoma cell survival under glucose deprivation by activating the serine synthesis pathway. Mechanistically, linc01564 acts as a competing endogenous RNA for miR-107/103a-3p and attenuates the inhibitory effect of miR-107/103a-3p on PHGDH, the rate-limiting enzyme of the serine synthesis pathway, thereafter leading to increased PHGDH expression. Furthermore, linc01564 is able to promote hepatocellular carcinogenesis via PHGDH. Together, these findings suggest that linc01564 is an important player in the regulation of metabolic adaption of cancer cells and also implicate linc01564 as a potential therapeutic target for cancer.

摘要：Cancer-associatedRNF43mutations lead to activation of β-catenin signaling through aberrantly increasing Wnt-receptor levels at the membrane. Importantly, inactivatingRNF43mutations have been suggested to render cancer cells sensitive to Wnt-based therapeutics. However, the extent to whichRNF43mutations lead to impaired regulation of Wnt/β-catenin signaling has been poorly investigated. Here, we observed that tumors with a functional mismatch repair system show a predominant 5′-location of truncatingRNF43mutations, suggesting C-terminal truncations such as the most commonly reported p.G659fs mutation, do not affect β-catenin signaling. In accordance, expressing C-terminal truncation mutants and wild-type RNF43, showed equal effects on β-catenin signaling, Wnt-receptor turnover, and DVL-binding. We confirmed these observations at endogenous levels by CRISPR-Cas9-mediated knockout of G659fs RNF43 expression in KM12 cells and generating comparable mutations in HEK293T cells. We could not confirm previous reports linking RNF43 to p53 and E-cadherin breakdown. Our data also suggest that only colorectal cancer cells harboring N-terminal mutations ofRNF43convey Wnt-dependency onto the tumor cells. Results of this study have potentially important clinical implications indicating that Wnt-based therapeutics should be applied cautiously in cancer patients harboringRNF43mutations.

摘要：BackgroundDysfunctional p53 signaling is one of the major causes of hepatocellular carcinoma (HCC) tumorigenesis and development, but the mechanisms underlying p53 inactivation in HCC have not been fully clarified. The role of Krüppel-associated box (KRAB)-type zinc-finger protein ZNF498 in tumorigenesis and the underlying mechanisms are poorly understood.MethodsClinical HCC samples were used to assess the association of ZNF498 expression with clinicopathological characteristics and patient outcomes. A mouse model in which HCC was induced by diethylnitrosamine (DEN) was used to explore the role of ZNF498 in HCC initiation and progression. ZNF498 overexpression and knockdown HCC cell lines were employed to examine the effects of ZNF498 on cellular proliferation, apoptosis, ferroptosis and tumor growth. Western blotting, immunoprecipitation, qPCR, luciferase assays and flow cytometry were also conducted to determine the underlying mechanisms related to ZNF498 function. ResultsZNF498 was found to be highly expressed in HCC, and increased ZNF498 expression was positively correlated with advanced pathological grade and poor survival in HCC patients. Furthermore, ZNF498 promoted DEN-induced hepatocarcinogenesis and progression in mice. Mechanistically, ZNF498 directly interacted with p53 and suppressed p53 transcriptional activation by inhibiting p53 Ser46 phosphorylation. ZNF498 competed with p53INP1 for p53 binding and suppressed PKCδ- and p53INP1-mediated p53 Ser46 phosphorylation. In addition, functional assays revealed that ZNF498 promoted liver cancer cell growth in vivo and in vitro in a p53-dependent manner. Moreover, ZNF498 inhibited p53-mediated apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation.ConclusionsOur results strongly suggest that ZNF498 suppresses apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation in hepatocellular carcinogenesis, revealing a novel ZNF498-PKCδ-p53INP1-p53 axis in HCC cells that would enrich the non-mutation p53-inactivating mechanisms in HCC.

摘要：Autophagy is a highly conserved programmed degradation process that regulates a variety of physiological and pathological activities in health, aging, and disease. To identify additional factors that modulate autophagy, we utilized serum-free starvation or Torin1 to induce autophagy in HeLa cells for unbiased mRNA-sequencing analysis and identified SNAI2, a crucial player in epithelial-to-mesenchymal transition and cancer progression, as a regulator of autophagy. Mechanistically, SNAI2 promotes autophagy by physically interacting with FOXO3 and enhancing FOXO3 binding affinity to its response elements in autophagy-related genes. Intriguingly, binding to the DNA targets appears necessary and sufficient for FOXO3 to antagonize its CRM1-dependent nuclear export, illustrating a critical role of DNA in regulating protein nuclear localization. Moreover, stress-elevated SNAI2 expression is mediated by FOXO3, which activatesSNAI2transcription by directly binding to its promoter. Herein, FOXO3 and SNAI2 form a coherent feed-forward regulatory loop to reinforce autophagy genes induction in response to energy stress. Strikingly, a dFoxO-Snail feed-forward circuit also regulates autophagy inDrosophila, suggesting this mechanism is evolutionarily conserved from fly to human.

摘要：Flag leaf angle impacts the photosynthetic capacity of densely grown plants and is thus an important agronomic breeding trait for crop architecture and yield. The hormone auxin plays a key role in regulating this trait, yet the underlying molecular and cellular mechanisms remain unclear. Here, we report that two rice (Oryza sativa) auxin response factors (ARFs), OsARF6 and OsARF17, which are highly expressed in lamina joint tissues, control flag leaf angle in response to auxin. Loss-of-function doubleosarf6 osarf17mutants displayed reduced secondary cell wall levels of lamina joint sclerenchymatous cells (Scs), resulting in an exaggerated flag leaf angle and decreased grain yield under dense planting conditions. Mechanical measurements indicated that the mutant lamina joint tissues were too weak to support the weight of the flag leaf blade, resembling the phenotype of the riceincreased leaf angle1(ila1) mutant. We demonstrate that OsARF6 and OsARF17 directly bind to theILA1promoter independently and synergistically to activate its expression. In addition, auxin-inducedILA1expression was dependent on OsARF6 and OsARF17. Collectively, our study reveals a mechanism that integrates auxin signaling with the secondary cell wall composition to determine flag leaf angle, providing breeding targets in rice, and potentially other cereals, for this key trait.

摘要：Signaling events triggered by hydrogen peroxide (H2O2) regulate plant growth and defense by orchestrating a genome-wide transcriptional reprogramming. However, the specific mechanisms that govern H2O2-dependent gene expression are still poorly understood. Here, we identify the Arabidopsis Mediator complex subunit MED8 as a regulator of H2O2responses. The introduction of themed8mutation in a constitutive oxidative stress genetic background (catalase-deficient,cat2) was associated with enhanced activation of the salicylic acid pathway and accelerated cell death. Interestingly,med8seedlings were more tolerant to oxidative stress generated by the herbicide methyl viologen (MV) and exhibited transcriptional hyperactivation of defense signaling, in particular salicylic acid- and jasmonic acid-related pathways. Themed8-triggered tolerance to MV was manipulated by the introduction of secondary mutations in salicylic acid and jasmonic acid pathways. In addition, analysis of the Mediator interactome revealed interactions with components involved in mRNA processing and microRNA biogenesis, hence expanding the role of Mediator beyond transcription. Notably, MED8 interacted with the transcriptional regulator NEGATIVE ON TATA-LESS, NOT2, to control the expression of H2O2-inducible genes and stress responses. Our work establishes MED8 as a component regulating oxidative stress responses and demonstrates that it acts as a negative regulator of H2O2-driven activation of defense gene expression.

摘要：The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammation and host defense; however, the underlying molecular mechanism remains unclear. Here, we show that myocyte enhancer factor 2?C (MEF2C) is essential for regulating M1 macrophage polarization in response to infection and inflammation. Global gene expression analysis demonstrated that MEF2C deficiency in macrophages downregulated the expression of M1 phenotypic markers and upregulated the expression of M2 phenotypic markers. MEF2C significantly promoted the expression of interleukin-12 p35 subunit(Il12a)and interleukin-12 p40 subunit(Il12b). Myeloid-specificMef2c-knockout mice showed reduced IL-12 production and impaired Th1 responses, which led to susceptibility toListeria monocytogenesinfection and protected against DSS-induced IBD in vivo. Mechanistically, we showed that MEF2C directly activated the transcription ofIl12aandIl12b. These findings reveal a new function of MEF2C in macrophage polarization and Th1 responses and identify MEF2C as a potential target for therapeutic intervention in inflammatory and autoimmune diseases

摘要：Rationale:Peritoneal metastasis is one of the most common and life-threatening metastases in gastric cancer patients. The disseminated gastric cancer cells forming peritoneal metastasis exhibit a variety of characteristics that contrast with those of adjacent epithelial cell of gastric mucosa and even primary gastric cancer cells. We hypothesized that the gene expression profiles of peritoneal foci could reveal the identities of genes that might function as metastatic activator.Methods:In this study, we show, usingin vitro, in vivo, in silicoand gastric cancer tissues studies in humans and mice, that Homoebox A11 (HOXA11) potently promote peritoneal metastasis of gastric cancer cells.Results:Its mechanism of action involves alternation of cancer stemness and subsequently enhancement of the adhesion, migration and invasion and anti-apoptosis. This is achieved, mainly, through formation of a positive feedback loop between HOXA11 and Stat3, which is involved in the stimulation of Stat3 signaling pathway.Conclusions:These observations uncover a novel peritoneal metastatic activator and demonstrate the association between HOXA11, Stat3 and cancer stemness of gastric cancer cells, thereby revealing a previously undescribed mechanism of peritoneal metastasis.Keywords:BBI608; HOXA11; Stat3; gastric cancer; peritoneal metastasis.

摘要：The limited treatment options for the increasing occurrence of Lassahemorrhagic feverin West Africa poses an urgent need for the discovery and development of novel therapeutics. Dietary supplements, especially natural products that are edible and safe for human use, are a good source of drug discovery with potential for uncovering novel applications. In this study, we tested 40 natural products of dietary supplements and identifiedcapsaicin, a common dietary supplement abundant in chili peppers, as an inhibitor ofLassa virus(LASV) entry with EC50of 6.9–10.0μmol/L using an HIV based pseudovirus platform. Capsaicin inhibits the entry of five LASV strains but not against theOld World arenaviruslymphocytic choriomeningitis virus(LCMV), showing a preferential activity against LASV. Capsaicin inhibits LASV entry by blocking the pH dependent viral fusion through affecting the stablesignal peptide(SSP)-GP2 transmembrane (GP2TM) region of the LASV surfaceglycoprotein. Mutational study revealed the key residues Ala25, Val431, Phe434 and Val435 in SSP-GP2TMregion in capsaicin's antiviral effect. This study for the first time reveals a direct acting antiviral effect of capsaicin against the hemorrhagic fever causing LASV, providing detailed interaction hot spots in the unique SSP-GP2TMinterface of LASV glycoprotein that is crucial in fusion inhibition, and offering a new strategy in discovering and developing antivirals from natural products that are safe for human use.

摘要：Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages.In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors.