Oncogenesis最新文献

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

Tetraspanins are transmembrane proteins that organize into functional structures known as tetraspanin-enriched microdomains, where they coordinate interactions with key partner proteins and modulate cellular processes such as adhesion, signaling, and motility. Among them, CD9 is a widely expressed member, also recognized as a classical marker of exosomes. Beyond its role in development and tissue homeostasis, CD9 has emerged as a modulator of the crosstalk between cancer cells and their microenvironment. It can contribute to processes such as cell migration, invasion, and resistance to therapy. Mechanistically, CD9 interacts with many partners including integrins, metalloproteinases, and signaling receptors to influence cell behavior. However, its functional contribution to tumor progression remains controversial. While CD9 expression is associated with enhanced dissemination in certain cancers, it appears to restrain motility and invasion in others. This likely reflects the complexity of its context-dependent functions, influenced by cell type, microenvironmental cues, and molecular partners. A deeper understanding of the regulatory mechanisms is therefore essential. In this review, we overview the tetraspanin family and summarize current knowledge on CD9 regulation and function across cancers, with a focus on leukemia. While its role in tumorigenesis remains debated, CD9 is a reliable biomarker of leukemic cells and can be used for diagnosis and MRD monitoring in acute lymphoblastic and myeloid leukemia, particularly in patients lacking molecular markers. We also discuss emerging therapeutic strategies that aim to target CD9 in cancer. CD9 gene regulation in cancer, and biological implication in acute lymphoblastic leukemia. Created with BioRender.com.

The deubiquitinating enzyme Ubiquitin specific peptidase 5 (USP5) has attracted substantial notice for its vital role in cancer progression. However, the USP5-mediated deubiquitination of corresponding protein substrates and its functional role in hepatocellular carcinoma (HCC) have not been fully investigated. Here, we demonstrated that USP5 expression was significantly elevated in HCC tissues. The overexpression of USP5 was closely associated with larger tumor sizes, more satellite nodules and tumor emboli, and predicted unfavorable clinical outcome in HCC patients as well. Functionally, USP5 facilitated cell proliferation, migration, and invasion, and induced lipid accumulation in vitro, along with enhanced tumor growth in vivo. Moreover, knockdown of USP5 expression showed a profound effect on lipidomic profiling, specially reduced the content of palmitic acid (PA). Treatment of PA could partially rescue the suppression of HCC mediated by USP5 knockdown. Further mechanistic investigation uncovered that Fatty acid synthase (FASN), the crucial enzyme catalyzing PA synthesis, was a downstream target of USP5. USP5 interacted with FASN, repressing the ubiquitination modification of FASN and preventing its degradation. Notably, the positive correlation between USP5 and FASN expression in HCC tissues was observed, and USP5 exerted oncogenic effects partly via FASN. Our findings revealed that USP5 promotes HCC progression through deubiquitinating FASN, and targeting the USP5-FASN-PA axis could potentially serve as a strategic approach for the therapy of HCC.

RNA modification, a prominent epigenetic mechanism, has been implicated in regulating RNA function, stability, processing, and interactions, including pseudouridylation, acetylation, and methylation. Recent evidence highlights that 5-methylcytosine (m5C) influences key cellular processes such as proliferation, differentiation, apoptosis, and stress responses by modulating RNA stability, translation, transcription, nuclear export, and cleavage. This review consolidates current insights into the role and mechanisms of m5C methylation across various tumor types, underscoring its pivotal involvement in post-transcriptional regulation and its profound effects on gene expression, cellular dynamics, and tumor biology. The mechanisms through which m5C methylation impacts tumor progression, including modulation of glucose and iron metabolism, as well as resistance to therapeutic agents, are also discussed. Finally, the review identifies critical future research avenues, focusing on elucidating the underlying mechanisms, developing targeted therapies, and advancing personalized medicine approaches to leverage m5C methylation in cancer treatment.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, exhibits anticancer properties by modulating cell membrane composition, inducing oxidative stress, and triggering ferroptosis. Acyl-CoA synthetase long chain family member 6 (ACSL6) catalyzes DHA activation, yet its role in tumor growth and tumor sensitivity to DHA treatment remains unclear. We characterized the role of ACSL6 in regulating cell growth and DHA sensitivity in vitro cancer cells and in vivo xenograft tumors. ACSL6 expression was positively associated DHA sensitivity and enhanced chemotherapy efficacy in both colorectal and breast cancer cell lines, as well as with improved responsiveness to standard treatments in patients with these cancers. ACSL6 suppressed cell growth, inhibited AKT/ERK signaling, reduced ATP production, and activated AMPK signaling, supporting its tumor-suppressive role. Importantly, ACSL6 knockdown increased GPX4 expression and colony growth, partially rescuing DHA-induced suppression, whereas ACSL6 overexpression enhanced DHA-mediated GPX4 reduction and colony inhibition, effects reversible by RSL3 or ferrostatin-1. Moreover, ACSL6 enhances DHA-induced lipid peroxidation. These support that ACSL6 enhances DHA-induced ferroptosis, leading to growth suppression. In vivo, DHA supplementation potentiated oxaliplatin-suppressed tumor growth in tumors with upregulated ACSL6 expression, accompanied by GPX4 reduction. Together, these findings highlight ACSL6 as a critical determinant of DHA sensitivity in cancer, underscoring its potential as a predictive biomarker for chemotherapy-DHA combination strategies. By modulating key metabolic and signaling pathways, ACSL6 could influence cellular susceptibility to ferroptosis and may guide therapeutic approaches that enhance chemotherapy through DHA supplementation.

Cancer stem cells (CSCs) are considered the head of a hierarchical organisation of carcinogenesis, exhibiting heightened cell survival properties, an ability to endlessly self-renew and undergo attenuated differentiation to maintain the bulk tumour population. The acquisition of cancer stem cell properties including dysregulated self-renewal and differentiation trajectories, is a dynamic disease-specific process underpinned by numerous genetic changes and signalling network aberrations. The bioactive sphingolipid, sphingosine 1-phosphate (S1P), has emerged as a key regulator of CSC biology. Historically, S1P has been associated with maintaining tissue homeostasis and immune responses, but recent studies have revealed that dysregulation of S1P-mediated cellular signalling plays important roles in CSC biology. This review provides an overview of the role of S1P in stem cell biology in both normal physiology and disease. It also describes approaches to target this signalling pathway, where aberrant, with the goal of eradicating the CSC population responsible for cancer initiation and progression, and importantly, patient relapse to many clinical therapeutics.

Rhabdomyosarcoma (RMS) is an aggressive cancer thought to arise from impaired myogenesis. This can be substantially overcome by increasing the levels of pannexin 1 (PANX1), a critical component of the myogenic program, but the mechanism involved is unknown. Using RNA-seq, we have previously found that overexpression of PANX1 dramatically reshapes the transcriptomic landscape of RMS including downregulation of a myogenic modulator, APOBEC2 (apolipoprotein B mRNA editing enzyme catalytic subunit 2). Following this clue, we investigated the role of APOBEC2 in the PANX1-mediated suppression of RMS malignancy. Here we show that, using a panel of patient-derived RMS cell lines and tumor specimens, APOBEC2 is expressed in RMS, but that its levels are lower than those in both differentiating myoblasts and skeletal muscle. In most RMS cell lines examined, APOBEC2 accumulates during proliferation and sustains their stem-like characteristics, as evidenced by its ability to promote the growth of spheroids upon increased expression. Yet, ectopic PANX1 expression led to a marked downregulation of APOBEC2 across a large proportion of RMS cell lines assessed. Strikingly, these were the same cells in which PANX1 triggers multinucleation. We further reveal that, like healthy myoblasts progressing through myogenesis, the multinucleation observed here in RMS cells results from cell fusion. Importantly, in RMS cells engineered to overexpress APOBEC2, PANX1 no longer enhances cell fusion, but its other anti-tumorigenic properties are still preserved. Collectively, our data indicate that PANX1 promotes RMS cell fusion by downregulating APOBEC2 expression, driving these tumor cells further into the myogenic program.

Bone metastsis in advanced breast cancer patients are usually osteolytic. A better understanding of the mechanisms in osteolytic metastasis is critical for the development of new therapies. YTH domain-containing family protein 3 (YTHDF3) has been reported to function as an N6-methyladenosine (m6A)-modified mRNA regulator. In this study, we found YTDHF3 expression was associated with clinical characteristics of breast cancer patients. YTHDF3 expression influenced the migration and invasion capacity of breast cancer cells in vitro and in vivo, and low expression of YTHDF3 suppressed cancer cell-induced osteoclast differentiation and osteolytic bone destruction. Moreover, we found YTHDF3 enhanced the translation of zinc finger E-box-binding protein 1 (ZEB1) and SMAD family member 5 (SMAD5) by reading the m6A modification sites in their mRNAs and further promoted the epithelial-mesenchymal transition (EMT) of breast cancer cells. Enhanced expression of ZEB1 promoted the transcription of bone morphogenetic protein inhibitors such as NOG, FST and CCN2, which boosts osteolytic metastasis. Furthermore, we newly found Wnt family member 5B (WNT5B) expression was regulated by ZEB1, also involved in osteolytic process. In conclusion, YTHDF3 plays an important role in osteolytic metastasis and it may serve as a potential prognostic biomarker and therapeutic target for breast cancer bone metastasis.

Aberrant Hedgehog signaling is a key driver of malignancies like medulloblastoma (MB), the most common pediatric brain tumor originating from cerebellar granule neuron progenitors with largely uncharacterized mechanisms. We found here that the G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1), is upregulated and correlates with the development of Sonic Hedgehog (SHH)-subtype MB. SHH and the downstream transcription factor Gli2 license the expression of CMKLR1, which promotes the growth and migration of cells by activating Gα(i)βγ and subsequently the PI3K/Akt signal pathway. SHH/Gli also transcriptionally represses Regulator of G Protein Signaling 16 (RGS16), a known suppressor of Gα(i). Meanwhile, CMKLR1/Gα(i) signaling inactivates protein kinase A (PKA), reduces PKA-catalyzed phosphorylation of Gli2, and circumvents its proteasomal degradation, thus forming a feedback circuit in medulloblastoma cells. Consistently, CMKLR1 ablation suppresses the in vivo development of SHH subtype MB, which is counteracted by further silencing of the PKA catalytic subunit. These findings provide novel insights into the oncogenic network of Hedgehog pathway-driven cancer.

Metastasis is the hallmark of lethal renal cell carcinoma (RCC), and the underlying mechanism driving RCC metastasis remains insufficiently understood. Amino acid metabolism remodeling plays a key role in the matastasis of RCC. In this study, we identified SLC6A19, a tryptophan transporter, as a novel suppressor gene of RCC, which is closely correlated with the metastasis and survival of RCC patients. Overexpression of SLC6A19 significantly inhibits RCC cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, SLC6A19 actively transports tryptophan into cells, facilitating de novo NAD⁺ biosynthesis, which in turn activates the NAD⁺-dependent deacetylase SIRT1. This activation drives the deacetylation of histone H3 at lysine 27 (H3K27), thereby restraining the transcription of NF-κB subunit p65, and effectively suppressing the epithelial-mesenchymal transition (EMT) of RCC cells. What's more, the inactivation of the transcription factor KLF4 is the key factor for the low expression of SLC6A19 in RCC cells. In conclusion, this study uncovers a novel key pathway that drives RCC invasion and metastasis, offering a promising therapeutic target for clinical intervention.