Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their ...inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential ...regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance.
Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on ...cardiovascular outcomes remain uncertain.
We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients 11.7% vs. 927 13.3%; hazard ratio, 0.87; 95% confidence interval CI, 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 8.2% vs. 663 9.5%; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 3.7% vs. 334 4.8%; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 6.2% vs. 529 7.6%; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.
Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).
Human galectin‐1 is a member of the galectin family, proteins with conserved carbohydrate‐recognition domains that bind galactoside. Galectin‐1 is highly expressed in various tumors and participates ...in various oncogenic processes. However, detailed descriptions of the function of galectin‐1 in urinary bladder urothelial carcinoma have not been reported. Our previous cohort investigation showed that galectin‐1 is associated with tumor invasiveness and is a possible independent prognostic marker of urinary bladder urothelial carcinoma. The present study aimed to clarify the relevance of galectin‐1 expression level to tumor progression and invasion. In order to decipher a mechanism for the contribution of galectin‐1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin‐1 expression by shRNA. Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity. Extensive signaling pathway studies indicated that galectin‐1 participated in bladder cancer cell invasion by mediating the activity of MMP9 through the Ras–Rac1–MEKK4–JNK–AP1 signaling pathway. Our functional analyses of galectin‐1 in urinary bladder urothelial carcinoma provided novel insights into the critical role of galectin‐1 in tumor progression and invasion. These results revealed that silencing the galectin‐1‐mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy.
Galectin‐1 participated in bladder cancer cell invasion through mediating the activity of matrix metalloproteinase 9 via Ras–Rac1–MAP/ERK kinase kinase 4–c‐Jun N‐terminal protein kinase–AP1 signaling pathway.
As tumor mutational burden (TMB) has been approved as a predictive biomarker for immune checkpoint inhibitors (ICIs), next-generation sequencing (NGS) TMB panels are being increasingly used ...clinically. However, only a few of them have been validated in clinical trials or authorized by administration. The harmonization and standardization of TMB panels are thus essential for clinical implementation. In this review, preanalytic, sequencing, bioinformatics and interpretative factors are summarized to provide a comprehensive picture of how the different factors affect the estimation of panel-based TMB. Among the factors, poor DNA quality, improper formalin fixation and residual germline variants after filtration may overestimate TMB, while low tumor purity may decrease the sensitivity of the TMB panel. In addition, a small panel size leads to more variability when comparing with true TMB values detected by whole-exome sequencing (WES). A panel covering a genomic region of more than 1Mb is more stable for harmonization and standardization. Because the TMB estimate reflects the sum of effects from multiple factors, deliberation based on laboratory and specimen quality, as well as clinical information, is essential for decision making.
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely ...unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
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•AMPKα facilitates TCA cycle by maintaining PDH complex activity•AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex•Activation of AMPKα-PDHA axis promotes tumor lung metastasis•AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients
Cai et al. demonstrate that phosphorylation of the catalytic subunit PDHA on Ser295 and S314 by AMPKα is essential for the maintenance of pyruvate dehydrogenase complex activity and TCA cycle. Activation of AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients and facilitates tumor lung metastasis.
Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are ...unclear.
Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.
Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.
Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.
Treatment of triple‐negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. ...Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen‐inducible gene‐6 (MIG‐6) has long been thought of as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncover that MIG‐6 is upregulated in TNBC and that MIG‐6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays reveal that MIG‐6 drives glucose metabolism reprogramming toward glycolysis. Mechanistically, MIG‐6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein expression and the subsequent upregulation of GLUT1 and other HIF1α‐regulated glycolytic genes, substantiating the comprehensive regulation of MIG‐6 in glucose metabolism. Moreover, our mouse studies demonstrate that MIG‐6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG‐6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC.
SYNOPSIS
MIG‐6 is upregulated in TNBC and promotes tumor growth by fueling glycolytic flux via the HIf1α‐Glut1 pathway.
MIG‐6 levels correlate with disease progression and bad prognosis in TNBC patients.
Depletion of MIG‐6 restricts TNBC cell proliferation and TNBC xenograft growth in mice.
MIG‐6 promotes aerobic glycolysis by promoting GLUT1 transcription.
MIG‐6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein, which in turn upregulates GLUT1.
MIG‐6 is upregulated in TNBC and promotes tumor growth by fueling glycolytic flux via the HIf1α‐Glut1 pathway.
Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 ...fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.
Twist has been shown to cause treatment failure, cancer progression, and cancer-related death. However, strategies that directly target Twist are not yet conceivable. Here we reveal that K63-linked ...ubiquitination is a crucial regulatory mechanism for Twist activation. Through an E3 ligase screen and biochemical studies, we unexpectedly identified that RNF8 functions as a direct Twist activator by triggering K63-linked ubiquitination of Twist. RNF8-promoted Twist ubiquitination is required for Twist localization to the nucleus for subsequent EMT and CSC functions, thereby conferring chemoresistance. Our histological analyses showed that RNF8 expression is upregulated and correlated with disease progression, EMT features, and poor patient survival in breast cancer. Moreover, RNF8 regulates cancer cell migration and invasion and cancer metastasis, recapitulating the effect of Twist. Together, our findings reveal a previously unrecognized tumor-promoting function of RNF8 and provide evidence that targeting RNF8 is an appealing strategy to tackle tumor aggressiveness and treatment resistance.
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•K63-linked ubiquitination activates Twist and EMT•RNF8 activates EMT and CSC self-renewal via Twist K63-linked ubiquitination•RNF8 overexpression in breast cancer predicts poor disease outcomes•RNF8 deficiency inhibits CSC self-renewal and cancer metastasis
RNF8 is known as a genome guardian. Lee et al. employed an E3 ligase screen, revealing RNF8 as an activator of Twist and cancer. RNF8 regulates cancer metastasis, and its overexpression is correlated with poor disease outcomes, opening up a new perspective on the cancer-promoting actions of DNA damage regulators.
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