BACKGROUND: PAF1/PD2 deregulation contributes to tumorigenesis, drug resistance, and cancer stem cell maintenance in Pancreatic Cancer (PC). Recent studies demonstrate that metabolic reprogramming plays a role in PC progression, but the mechanism is poorly understood. Here, we focused on examining the role of PAF1/PD2 in the metabolic rewiring of PC.
METHODS: Cell lines were transfected with shRNAs to knockdown PAF1/PD2. Metabolic genes regulated by PAF1/PD2 were identified by qPCR/western blot, and metabolic assays were performed. Immunoprecipitations/ChIP were performed to identify PAF1/PD2 protein partners and confirm PAF1/HIF1α sub-complex binding to LDHA.
RESULTS: PAF1 and LDHA showed progressively increased expression in human pancreatic tumor sections. Aerobic glycolysis genes were downregulated in PAF1-depleted PC cells. Metabolic assays indicated a decreased lactate production and glucose uptake in knockdown cells. Furthermore, PAF1/PD2 depletion showed a reduced glycolytic rate and increased oxidative phosphorylation by ECAR and OCR analysis. Interestingly, we identified that HIF1α interacts and co-localizes with PAF1, specifically in PC cells. We also observed that the PAF1/PD2-HIF1α complex binds to the LDHA promoter to regulate its expression, reprogramming the metabolism to utilize the aerobic glycolysis pathway preferentially.
CONCLUSIONS: Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.

BACKGROUND: Alzheimer\'s disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid β slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation.
METHODS: In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice.
RESULTS: Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid β deposits.
CONCLUSIONS: These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.

Epithelial ovarian cancer (EOC), a leading cause of gynecological cancer-related morbidity and mortality and the most common type of ovarian cancer (OC), is widely characterized by alterations in the Epidermal Growth Factor (EGF) signaling pathways. The phenomenon of metastasis is largely held accountable for the majority of EOC-associated deaths. Existing literature reports substantiate evidence on the indispensable role of metabolic reprogramming, particularly the phenomenon of the \'Warburg effect\' or aerobic glycolysis in priming the cancer cells towards Epithelial to Mesenchymal transition (EMT), subsequently facilitating EMT. Considering the diverse roles of growth factor signaling across different stages of oncogenesis, our prime emphasis was laid on unraveling mechanistic details of EGF-induced \'Warburg effect\' and resultant metastasis in EOC cells. Our study puts forth Ets1, an established oncoprotein and key player in OC progression, as the prime metabolic sensor to EGF-induced cues from the tumor microenvironment (TME). EGF treatment has been found to induce Ets1 expression in OC cells predominantly through the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) pathway activation. This subsequently results in pronounced glycolysis, characterized by an enhanced lactate production through transcriptional up-regulation of key determinant genes of the central carbon metabolism namely, hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4). Furthermore, this study reports an unforeseen combinatorial blockage of HK2 and MCT4 as an effective approach to mitigate cellular metastasis in OC. Collectively, our work proposes a novel mechanistic insight into EGF-induced glycolytic bias in OC cells and also sheds light on an effective therapeutic intervention approach exploiting these insights.

MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.

Prostate cancer remains the most prevalent malignancy diagnosed in men worldwide. Epithelial cell transforming sequence 2 (ECT2) is an oncogene involved in the progression of human tumors. The present study aimed to explore the involvement of ECT2 in prostate cancer and its participation in the malignant progression of prostate cancer. ECT2 expression in prostate cancer cell lines was examined via reverse transcription-quantitative PCR and western blotting. The effects of knockdown of ECT2 expression in PC-3 cells on cellular biological behaviors, including proliferation, migration and invasion, were examined using Cell Counting Kit-8, colony formation, wound healing and Transwell assays. The glycolysis level was determined based on the lactate release, glucose uptake, oxygen consumption rate and extracellular acidification rate. The binding relationship between ECT2 and ETS1 was verified using luciferase reporter and chromatin immunoprecipitation assays. The results indicated that ECT2 was highly expressed in prostate cancer cell lines. Knockdown of ECT2 expression could inhibit cell proliferation, migration, invasion and glycolysis. In addition, the transcription factor ETS1 could directly bind to the ECT2 promoter and positively regulate ECT2 expression. These data were combined with the results of rescue experiments and demonstrated that the inhibitory effects of the knockdown of ECT2 expression on the malignant behavior and glycolysis of prostate cancer cells were partially reversed by ETS1 overexpression. In conclusion, ETS1 induced transcriptional upregulation of ECT2 and enhanced the malignant biological behaviors of prostate cancer cells, thereby promoting the progression of prostate cancer. This evidence provides a theoretical basis for the treatment of prostate cancer.

Aerobic glycolysis is one of the major hallmarks of malignant tumors. This metabolic reprogramming benefits the rapid proliferation of cancer cells, facilitates the formation of tumor microenvironment to support their growth and survival, and impairs the efficacy of various tumor therapies. Therefore, the elucidation of the mechanisms driving aerobic glycolysis in tumors represents a pivotal breakthrough in developing therapeutic strategies for solid tumors. HIF1α serves as a central regulator of aerobic glycolysis with elevated mRNA and protein expression across multiple tumor types. However, the mechanisms contributing to this upregulation remain elusive. This study reports the identification of a novel HIF1α super enhancer (HSE) in multiple cancer cells using bioinformatics analysis, chromosome conformation capture (3C), chromatin immunoprecipitation (ChIP), and CRISPR/Cas9 genome editing techniques. Deletion of HSE in cancer cells significantly reduces the expression of HIF1α, glycolysis, cell proliferation, colony and tumor formation ability, confirming the role of HSE as the enhancer of HIF1α in cancer cells. Particularly, we demonstrated that STAT3 promotes the expression of HIF1α by binding to HSE. The discovery of HSE will help elucidate the pathways driving tumor aerobic glycolysis, offering new therapeutic targets and potentially resolving the bottleneck in solid tumor treatment.

This study delves into the molecular intricacies of hypopharyngeal squamous cell carcinoma (HSCC), specifically focusing on the pivotal role played by ETS translocation variant 4 (ETV4) in aerobic glycolysis. The objective is to uncover new targets for early diagnosis and treatment of HSCC. ETV4 expression in HSCC tissues was rigorously examined, revealing its association with patient survival. Through comprehensive experimentation, we demonstrated that ETV4 activation promotes HSCC cell proliferation and invasion while inhibiting apoptosis. Furthermore, in vivo experiments confirmed the tumor-promoting effect of ETV4 activation. The study elucidated the binding of ETV4 to the NSUN2 promoter and its influence on PKM2 expression, thereby regulating glycolysis and cellular functions in HSCC.

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes.

OBJECTIVE: Multiple myeloma (MM) is a deadly plasma cell malignancy with elusive pathogenesis. N6-methyladenosine (m6A) is critically engaged in hematological malignancies. The function of KIAA1429, the largest component of methyltransferases, is unknown. This study delved into the mechanism of KIAA1429 in MM, hoping to offer novel targets for MM therapy.
METHODS: Bone marrow samples were attained from 55 MM patients and 15 controls. KIAA1429, YTHDF1, and FOXM1 mRNA levels were detected and their correlation was analyzed. Cell viability, proliferation, cell cycle, and apoptosis were testified. Glycolysis-enhancing genes (HK2, ENO1, and LDHA), lactate production, and glucose uptake were evaluated. The interaction between FOXM1 mRNA and YTHDF1, m6A-modified FOXM1 level, and FOXM1 stability were assayed. A transplantation tumor model was built to confirm the mechanism of KIAA1429.
RESULTS: KIAA1429 was at high levels in MM patients and MM cells and linked to poor prognoses. KIAA1429 knockdown restrained MM cell viability, and proliferation, arrested G0/G1 phase, and increased apoptosis. KIAA1429 mRNA in plasma cells from MM patients was positively linked with to glycolysis-enhancing genes. The levels of glycolysis-enhancing genes, glucose uptake, and lactate production were repressed after KIAA1429 knockdown, along with reduced FOXM1 levels and stability. YTHDF1 recognized KIAA1429-methylated FOXM1 mRNA and raised FOXM1 stability. Knockdown of YTHDF1 curbed aerobic glycolysis and malignant behaviors in MM cells, which was nullified by FOXM1 overexpression. KIAA1429 knockdown also inhibited tumor growth in animal experiments.
CONCLUSIONS: KIAA1429 knockdown reduces FOXM1 expression through YTHDF1-mediated m6A modification, thus inhibiting MM aerobic glycolysis and tumorigenesis.

Idiopathic pulmonary fibrosis (IPF) represents a severe interstitial lung disease characterized by limited therapeutic interventions. Recent study has suggested that sinomenine (SIN), an alkaloid derived from the roots of Sinomenium acutum, demonstrates efficacy in interrupting aerobic glycolysis, a predominant metabolic pathway in myofibroblasts. However, its pharmacological potential in the context of pulmonary fibrosis remains inadequately explored. In the present study, we established a bleomycin (BLM)-induced pulmonary fibrosis mouse model and subjected the mice to a one-week regimen of SIN treatment to assess its efficacy. Additionally, a TGF-β1-induced primary lung fibroblast model was employed to investigate the molecular mechanism underlying the effects of SIN. Our observations revealed robust anti-pulmonary fibrosis properties associated with SIN treatment, as evidenced by reduced extracellular matrix deposition, diminished hydroxyproline contents, improved Ashcroft scores, and enhanced lung function parameters. Furthermore, SIN administration significantly impeded TGF-β1-induced fibroblast-to-myofibroblast differentiation. Mechanistically, SIN exerted its beneficial effects by mitigating aerobic glycolysis, achieved through the inhibition of the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3). Notably, the protective effects of SIN on fibroblasts were reversed upon ectopic overexpression of Pfkfb3. In conclusion, our data underscore the potential of SIN to attenuate fibroblast-to-myofibroblast differentiation by modulating Pfkfb3-associated aerobic glycolysis and SIN emerges as a promising anti-fibrotic agent for pulmonary fibrosis in clinical practice.