The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.

RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in vitro and in vivo. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.

Association between composite dietary antioxidant index and kidney stone prevalence in adults: data from National Health and Nutrition Examination Survey (NHANES, 2007-2018).

Background: The high prevalence of kidney stones in adults worldwide has prompted research into potential interventions, one of which involves exploring the consumption of antioxidants that may confer protective effects. However, the relationship between the composite dietary antioxidant index (CDAI), a crucial measure used to assess an individual's overall antioxidant capacity from daily dietary intake, and kidney stones remains unclear. Therefore, we conducted cross-sectional analysis to examine the association between CDAI and kidney stone prevalence. Methods: The analysis was conducted utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Antioxidant intake was derived from two 24-h dietary recalls surveys, while CDAI, a comprehensive measure that includes antioxidants like vitamins A, C, and E, zinc, selenium, and carotenoids, was calculated. Multivariate logistic regression and restricted cubic spline (RCS) regression were utilized to examine the association between CDAI and the prevalence of kidney stones. Results: The study included a total of 28,516 participants, with 2,748 individuals having a history of kidney stones. The median of CDAI was -0.01 (-2.02, 2.37). Individuals in the fourth quartile of CDAI exhibited a significantly lower prevalence of kidney stones compared to those in the first quartile (Odds Ratio [OR] = 0.769 [0.633-0.935]), even after adjusting for potential confounding factors (including age, sex, race, education level, poverty income ratio, smoking status, drinking status, body mass index (BMI), energy intake levels, physical activity level, serum calcium concentration, estimated glomerular filtration rate (eGFR), hypertension, diabetes and supplement use). The RCS analysis revealed a non-linear relationship between CDAI and kidney stone prevalence, with inflection points identified at 0.06 (p for non-linearity = 0.039). Subgroup analysis demonstrated consistent CDAI-kidney stone prevalence associations across all subsets. Furthermore, a significant inverse correlation was observed between CDAI and inflammatory markers. Conclusion: This study provides evidence supporting a reciprocal correlation between adult dietary antioxidant intake, as measured by CDAI, and kidney stone prevalence. These findings emphasize the potential benefits of consuming dietary antioxidants in lowering the risk of kidney stone formation.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

An Epigenomic fingerprint of human cancers by landscape interrogation of super enhancers at the constituent level.

Super enhancers (SE), large genomic elements that activate transcription and drive cell identity, have been found with cancer-specific gene regulation in human cancers. Recent studies reported the importance of understanding the cooperation and function of SE internal components, i.e., the constituent enhancers (CE). However, there are no pan-cancer studies to identify cancer-specific SE signatures at the constituent level. Here, by revisiting pan-cancer SE activities with H3K27Ac ChIP-seq datasets, we report fingerprint SE signatures for 28 cancer types in the NCI-60 cell panel. We implement a mixture model to discriminate active CEs from inactive CEs by taking into consideration ChIP-seq variabilities between cancer samples and across CEs. We demonstrate that the model-based estimation of CE states provides improved functional interpretation of SE-associated regulation. We identify cancer-specific CEs by balancing their active prevalence with their capability of encoding cancer type identities. We further demonstrate that cancer-specific CEs have the strongest per-base enhancer activities in independent enhancer sequencing assays, suggesting their importance in understanding critical SE signatures. We summarize fingerprint SEs based on the cancer-specific statuses of their component CEs and build an easy-to-use R package to facilitate the query, exploration, and visualization of fingerprint SEs across cancers.

Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.

RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to EGFR tyrosine kinase inhibitors. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.

Comparison of Helicobacter pylori positive and negative gastric cancer via multi-omics analysis.

Helicobacter pylori (H. pylori) has been regarded as a definite carcinogenic bacterium for gastric cancer (GC). This multi-omics research was designed to investigate the genetic, microbial, and metabolic changes of GC patients when they are infected with H. pylori. We first mined The Cancer Genome Atlas Stomach Adenocarcinoma (STAD) data to identify the key genes and critical pathways in H. pylori-positive individuals with GC compared to H. pylori-negative individuals with GC. Then, fresh stool samples were collected from GC individuals screened for eligibility, and we analyzed the microbial changes and metabolite alterations between H. pylori-positive and H. pylori-negative GC individuals. Finally, we tried to explore the interaction between key gut flora and metabolite changes in GC patients infected with H. pylori. We identified three genes (GCG, APOA1, and IGFBP1) with significant relevance to H. pylori infection, and the survival monogram based on the three H. pylori-related genes showed good predictive ability for overall survival among GC individuals. 16S rRNA sequencing showed that the abundance of Escherichia-Shigella, Bacteroides, Enterococcus, and Lactobacillus was upregulated in GC cases with H. pylori at the level of genus. There exists a great difference in alpha and beta diversity between H. pylori group and non-H. pylori group. The untargeted metabolome analysis identified 295 significant fecal metabolites, and the levels of penitrem E, auberganol, stercobilinogen, and lys thr are upregulated in the H. pylori group. Finally, correlation analysis showed that there exists a significant correlation between the fecal metabolites and gut bacterial strains. This is the first clinical research to investigate the difference between GC patients with H. pylori and GC patients without H. pylori via multi-omics analysis. 16S rRNA sequencing along with untargeted metabolomics demonstrated decreased microbial diversity and metabolic dysregulation in gastric carcinoma individuals with H. pylori infection.IMPORTANCEThis is the first clinical research to systematically expound the difference between gastric cancer (GC) individuals with Helicobacter pylori and GC individuals without H. pylori from the perspective of multi-omics. This clinical study identified significant genes, microbes, and fecal metabolites, which exhibited nice power for differentiating GC individuals with H. pylori infection from GC individuals without H. pylori infection. This study provides a crucial basis for a better understanding of eradication therapy among the GC population.

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.

[Adaptability of Broussonetia papyrifera to sewage sludge and its characteristics of nutrient and heavy metal uptake and accumulation]. / æž„æ ‘çš„æ±¡æ³¥é€‚åº”æ€§åŠå »åˆ†å’Œé‡é‡‘å±žå¸æ”¶ç´¯ç§¯ç‰¹å¾.

Broussonetia papyrifera, an important fast-growing economic tree species in China, has the advantages of strong adaptability, high-biomass, and high bioconcentration of heavy metals. Sewage sludge contains a great deal of nutrients and heavy metals. Planting B. papyrifera with sewage sludge can achieve the goals of sewage sludge remediation as well as resources production of B. papyrifera. A pot experiment was conducted to investigate growth, uptake and accumulation of nutrient and heavy metal in different organs (root, stem, leaf) of B. papyrifera, with treatments of control (lateritic red soil), 50% sewage sludge (mixed substrates of 50% sewage sludge and 50% lateritic red soil based on weight) and 100% sewage sludge. The comprehensive evaluation of capacity of uptake and accumulation was also carried out by principal component analysis and membership function. The results showed that B. papyrifera could grow normally in both 50% and 100% sewage sludge substrates, with higher plant height and biomass than that in the control, especially in 100% sewage sludge substrate. The quality index in 100% sewage sludge substrate (1.02) was 4.3 times and 2.4 times as that of the control and 50% sewage sludge substrate, respectively. The content of N in different organs and P in stem increased significantly in both 50% and 100% sewage sludge substrates. The content of K in stem and leaf was significantly decreased in 100% sewage sludge substrate, which were significant lower than that of control. The uptake of heavy metals such as Cu, Zn, Pb, Cd, Ni for B. papyrifera were mainly through roots. There was positive correlation between the content of heavy metals in root and sewage sludge ratio. The content of Pb and Cd in leaves were lower than the limit value of Hygienic Standard For Feeds (GB 13078-2017). The capacity for absorption and accumulation of Cd was better than that of other heavy metals. Compared with the control, rootretention rates of Zn, Pb and Cd significantly increased in both 50% and 100% sewage sludge substrates (57.8%-85.8%), while Cu and Ni significantly increased in 100% sewage sludge substrate (67.5% and 74.8%). Nutrient and heavy metal accumulations in total plant in both 50% and 100% sewage sludge substrates were significantly higher than that in the control, with 100% sewage sludge substrate being significantly higher than that in 50% sewage sludge substrate. Compared with 50% sewage sludge substrate, the increment rates of nutrient and heavy metal accumulations in different organs as well as total plants in 100% sewage sludge substrates were greatly increased. The rank of comprehensive evaluation scores of adaptability, element uptake and accumulation was in an order: 100% sewage sludge substrate (0.848) > 50% sewage sludge substrate (0.344) > control (0.080). With good adaptability to sewage sludge, B. papyrifera could grow normally in sewage sludge andeffectively absorb and fix nutrients and heavy metals. It is feasible to plant B. papyrifera into the sewage sludge for remediation of sewage sludge and resource production.

TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway.

The dynamics of mitochondrial biogenesis regulation is critical in maintaining cellular homeostasis for immune regulation and tumor prevention. Here, we report that mitochondrial biogenesis disruption through TFAM reduction significantly impairs mitochondrial function, induces autophagy, and promotes esophageal squamous cell carcinoma (ESCC) growth. We found that TFAM protein reduction promotes mitochondrial DNA (mtDNA) release into the cytosol, induces cytosolic mtDNA stress, subsequently activates the cGAS-STING signaling pathway, thereby stimulating autophagy and ESCC growth. STING depletion or mtDNA degradation by DNase I abrogates mtDNA stress response, attenuates autophagy, and decreases the growth of TFAM depleted cells. In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.

CircATIC inhibits esophageal carcinoma progression and promotes radiosensitivity by elevating RHCG through sponging miR-10-3p.

BACKGROUND: Circular RNAs (circRNAs) are implicated in the progression and radiosensitivity of human cancers, including esophageal carcinoma (ESCA). In this study, we aimed to explore the functions of circRNA 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (circATIC) in ESCA progression. METHODS: CircATIC expression, miR-10b-3p and Rh family C glycoprotein (RHCG) were examined via quantitative real-time polymerase chain reaction (qRT-PCR), western blot assay or immunohistochemistry (IHC) assay. 5'-ethynyl-2'-deoxyuridine (EdU), wound-healing, transwell, and cell colony formation assays and flow cytometry analysis were conducted to evaluate cell proliferation, migration, invasion, radiosensitivity and apoptosis, respectively. Dual-luciferase reporter assay and RNA pulldown assay were conducted to analyze the relationships among circATIC, miR-10b-3p and RHCG. A murine xenograft model assay was performed to explore the functions of circATIC in tumor formation and radiosensitivity in vivo. RESULTS: CircATIC was decreased in ESCA. CircATIC overexpression suppressed cell proliferation, migration and invasion and promoted radiosensitivity and apoptosis in ESCA cells in vitro and repressed tumor formation and radioresistance in vivo. Functionally, circATIC served as the sponge for miR-10b-3p, which directly targeted RHCG. MiR-10b-3p elevation reversed circATIC-mediated effect on ESCA cell progression. Moreover, miR-10b-3p inhibition suppressed cell growth and metastasis and enhanced radiosensitivity in ESCA cells by targeting RHCG. CONCLUSIONS: Overexpression of circATIC hampered ESCA progression and promoted radiosensitivity depending on the regulation of miR-10b-3p and RHCG.

Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.

BACKGROUND: Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression. RESULTS: We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth. CONCLUSIONS: Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

Acetylation-dependent regulation of BRAF oncogenic function.

Aberrant BRAF activation, including the BRAFV600E mutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAFV600E inhibitor resistance in BRAFV600E harboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1 deficiency as potential biomarkers to determine ERK activation in melanomas.

RAF-MEK-ERK pathway in cancer evolution and treatment.

The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAFV600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.

Integrative Analysis Identifies Multi-Omics Signatures That Drive Molecular Classification of Uveal Melanoma.

By iCluster analysis, we found that the integrative molecular classification of the UM was primarily driven by DNA copy number variation on chromosomes 3, 6 and 8, differential methylation and expression of genes involved in the immune system, cell morphogenesis, movement and migration, and differential mutation of genes including GNA11, BAP1, EIF1AX, SF3B1 and GNAQ. Integrative analysis revealed that pathways including IL6/JAK/STAT3 signaling, angiogenesis, allograft rejection, inflammatory response and interferon gamma response were hypomethylated and up-regulated in the M3 iSubtype, which was associated with a worse overall survival, compared to the D3 iSubtype. Using two independent gene expression datasets, we demonstrated that the subtype-driving genes had an excellent prognostic power in classifying UM into high- or low-risk groups for metastasis. Integrative analysis of UM multi-omics data provided a comprehensive view of UM biology for understanding the underlying mechanism leading to UM metastasis. The concordant molecular alterations at multi-omics levels revealed by our integrative analysis could be used for patient stratification towards personalized management and surveillance.

Long non-coding RNA small nucleolar RNA host gene 7 facilitates the proliferation, migration, and invasion of esophageal cancer cells by regulating microRNA-625.

BACKGROUND: Esophageal cancer (EC) is a highly aggressive malignant tumor, of which esophageal squamous cell carcinoma (ESCC) constitutes the main subtype. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) has been extensively studied in many tumors and has been confirmed to be an oncogene; however, it has yet to be investigated in an ESCC study. Therefore, this study intended to uncover the role of SNHG7 in ESCC. METHODS: Quantitative real-time polymerase chain reaction was applied to measure the expression levels of SNHG7 and miR-625 in ESCC tumor tissues and cell lines. Cell Counting Kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, scratch assay, and Transwell assay were conducted to assess the proliferation, migration, and invasion ESCC cell. We verified the interaction between SNHG7 and miR-625 by performing the dual luciferase reporter gene experiment. RESULTS: Compared to that in adjacent normal tissues and HET1A cell lines, the expression level of SNHG7 in ESCC tumor tissues and ESCC cell lines was up-regulated, while the expression level of miR-625 was down-regulated. ESCC cell proliferation, migration, and invasion were significantly promoted by SNHG7 overexpression but inhibited by silencing of SNHG7. Further, luciferase reporter gene experiments confirmed that SNHG7 interacted with miR-625, and rescue experiments showed that SNHG7 promoted the malignant phenotype by inhibiting miR-625. CONCLUSIONS: SNHG7 is up-regulated in ESCC tumor tissues and cell lines, while miR-625 is expressed at a low level. SNHG7 is able to facilitate the proliferation, migration, and invasion of ESCC cells by targeting miR-625.

Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.

Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma.

TEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclear-encoded transcription elongation factor in the transcription of mitochondrial genome. Our bioinformatics analysis of TCGA data revealed an aberrant over-expression of TEFM in hepatocellular carcinoma (HCC). We analyzed its biological effects and clinical significance in this malignancy. TEFM expression was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry analysis in HCC tissues and cell lines. The effects of TEFM on HCC cell growth and metastasis were determined by cell proliferation, colony formation, flow cytometric cell cycle and apoptosis, migration, and invasion assays. TEFM expression was significantly increased in HCC tissues mainly caused by down-regulation of miR-194-5p. Its increased expression is correlated with poor prognosis of HCC patients. TEFM promoted HCC growth and metastasis both in vitro and in vivo by promoting G1-S cell transition, epithelial-to-mesenchymal transition (EMT), and suppressing cell apoptosis. Mechanistically, TEFM exerts its tumor growth and metastasis promoting effects at least partly through increasing ROS production and subsequently by activation of ERK signaling. Our study suggests that TEFM functions as a vital oncogene in promoting growth and metastasis in HCC and may contribute to the targeted therapy of HCC.