Findings reveal that the RNF114-PACSIN3-GLUT1 axis regulates glucose uptake and metabolic reprogramming in HCC, thereby promoting tumor progression and contributing to therapy resistance.
Abstract
Purpose
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with current therapies often limited by significant drug resistance. Owing to the Warburg effect, targeting cancer-specific metabolic vulnerabilities is a promising therapeutic strategy. This study aims to investigate the role of RNF114 in HCC progression and its regulatory mechanism, as well as its clinical translational potential as a therapeutic target.
Methods
We evaluated the clinical significance of RNF114 using tissue microarrays and database analysis. RNF114 function in promoting HCC progression by regulating glucose uptake was investigated using knockdown experiments in cell lines and subcutaneous xenograft models. Furthermore, a therapeutic xenograft model was employed to assess the potential of RNF114 knockdown in overcoming Sorafenib resistance.
Results
RNF114 was highly expressed in HCC and correlated with poor prognosis. Knockdown of RNF114 significantly suppressed HCC cell proliferation, migration, invasion, and glycolysis. Co-immunoprecipitation identified PACSIN3 as a key substrate of RNF114. RNF114 interacted with the SH3 domain of PACSIN3, promoting its ubiquitination and proteasomal degradation. Subcellular fractionation revealed that the F-BAR domain of PACSIN3 facilitated GLUT1 vesicular trafficking. Consequently, RNF114 impaired this process, leading to increased plasma membrane retention of GLUT1 and enhanced glycolytic flux. Consistently, in both HCC cells and subcutaneous xenograft models, RNF114 knockdown sensitized tumors to Sorafenib treatment.
Conclusions
Collectively, our findings reveal that the RNF114-PACSIN3-GLUT1 axis regulates glucose uptake and metabolic reprogramming in HCC, thereby promoting tumor progression and contributing to therapy resistance. Targeting this signaling axis provides a novel insight into metabolic therapy for HCC.
LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Yuxin Zhang, Weiqi Xu, Fangling Cheng et al.· Cancer Drug Resistance· 0 citations
HCC (Hepatocellular carcinoma) is one of the malignant tumors with high morbidity and mortality worldwide. Its pathogenesis is complex and the efficacy of existing treatments is limited. Therefore, in-depth exploration of key regulatory molecules and their mechanisms is of great significance for the early diagnosis and targeted therapy of HCC. In this study, HCC cell lines Huh-7 and HepG2 were used as research models to systematically investigate the biological function and molecular regulatory mechanism of FAM117B (family with sequence similarity 117 member B) in HCC progression through gene knockdown and overexpression, cell functional assays, co-immunoprecipitation coupled with mass spectrometry, post-translational modification detection, transcriptome sequencing and nude mouse subcutaneous tumorigenesis assays. High FAM117B expression predicted poor prognosis and positively correlated with pathological grade; functionally, FAM117B exhibited robust oncogenic activity, where its knockdown suppressed proliferation, clonogenicity, invasion, and migration, and its overexpression enhanced these phenotypes. Mechanistic studies revealed that FAM117B directly physically interacted with NAT10 (N-acetyltransferase 10), an acetyltransferase, forming a bidirectional regulatory loop: on the one hand, FAM117B maintained the protein stability of NAT10 by inhibiting its K48-linked ubiquitination and subsequent proteasomal degradation; on the other hand, NAT10, as a key acetyltransferase, specifically mediated the acetylation of FAM117B at lysine 429, providing a molecular basis for the functional role of FAM117B. Transcriptome sequencing and molecular verification demonstrated that the FAM117B/NAT10 axis targeted and regulated JAK2 (Janus kinase 2) expression, activated the downstream JAK-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and thereby drove the malignant biological behaviors of HCC cells. In vivo, dual knockdown of FAM117B and NAT10 significantly reduced xenograft growth, decreased Ki67, and increased apoptosis; notably, NAT10 depletion abrogated the tumor-promoting effects of FAM117B overexpression. In conclusion, this study reveals the molecular mechanism by which FAM117B promotes HCC progression via forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 signaling pathway through acetylation modification, providing a novel potential target and theoretical basis for targeted therapy of HCC.
Hepatocellular carcinoma (HCC) remains one of the most aggressive and lethal malignancies worldwide, with high rates of metastasis and recurrence contributing to its poor prognosis. There is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop effective therapeutic strategies. Metabolic reprogramming, especially aerobic glycolysis known as the Warburg effect, is a well-established hallmark of cancer. Concurrently, cancer stem cells (CSCs) play crucial roles in tumor initiation, therapy resistance, and recurrence. However, the involvement of long non-coding RNAs (lncRNAs) in linking metabolic alterations and stemness remains poorly understood. In this investigation, we identified LINC02041 as a significantly upregulated lncRNA in HCC tissues and demonstrated its oncogenic role in promoting cell proliferation. We found that STAT3 transcriptionally activates LINC02041 expression. Mechanistically, LINC02041 enhances the stability of SRSF1 protein by suppressing its ubiquitin-mediated degradation, thereby facilitating HCC cell proliferation, migration, glycolytic metabolism, and acquisition of stem-like properties. Our findings delineate a novel STAT3/LINC02041/SRSF1 regulatory axis that coordinately modulates glycolytic reprogramming and stemness maintenance in hepatocarcinogenesis. This study not only advances our understanding of HCC pathophysiology but also identifies LINC02041 as a promising prognostic biomarker and a compelling therapeutic target for novel therapeutic strategies against this aggressive malignancy.
Mingjia Cheng, Anqi Cheng, Chenglong Li et al.· Cells· 0 citations
It is confirmed that MRPS30 inhibits ferroptosis by upregulating Glutathione Peroxidase 4(GPX4), thereby promoting the malignant progression of HCC and resistance to lenvatinib, and confirmed that ferroptosis is a promising therapeutic strategy for HCC treatment.
Weihui Guo, Yu Weng, Fang Wu et al.· International Journal of Bio...· 0 citations
It is revealed that the LINC02038/miR‐506‐3p/ATP7A axis played a crucial oncogenic role in HCC by driving tumor progression and modulating cuproptosis, and represents a promising prognostic biomarker and a potential therapeutic target for HCC intervention.
Zhe Liu, Weixi Shan, Wen-Yu Zhou et al.· Journal of biochemical and m...· 0 citations
BACKGROUND
Hepatocellular carcinoma (HCC) frequently develops in the setting of chronic hepatitis B virus (HBV) infection, yet the molecular events shared by HBV-related liver injury and malignant transformation remain incompletely characterized. Recent studies of cuproptosis indicate that copper overload can disturb mitochondrial metabolic programs in tumor cells. This rationale prompted us to examine copper-responsive alterations across chronic HBV-related liver injury and HCC.
METHODS
TCGA-LIHC and GSE230397 datasets were analyzed to identify shared differentially expressed genes between HCC and chronic HBV infection. Functional enrichment, ssGSEA, WGCNA, and five machine-learning algorithms were used to screen cuproptosis-associated candidate genes. C1R expression, prognosis, immune infiltration, and immune checkpoint correlations were assessed. Experimental validation was then performed in HCC cell lines by manipulating C1R expression and assessing copper modulation, HIF-1α rescue, intracellular localization, protein expression, oxidative stress, cell motility, HIF-1α stability, proteasome inhibition, and ubiquitination.
RESULTS
The integrated analysis identified 423 genes with concordant dysregulation in the HBV and HCC datasets. These genes were linked to metal ion response, oxidative stress, and copper-associated biological processes. Cuproptosis-related scores were lower in both HCC tissues and HBV-infected liver samples. Integrative WGCNA and machine-learning analyses identified C1R as the only shared cuproptosis associated candidate gene. C1R was downregulated in HCC and associated with survival, immune infiltration, and immune checkpoint molecules. Functionally, C1R overexpression increased FDX1, DLAT, and DLST expression, elevated ROS accumulation, and suppressed HCC cell migration and invasion, whereas C1R knockdown produced opposite effects. Copper chelation with TTM weakened the effects of C1R overexpression, whereas combined elesclomol and CuCl₂ treatment intensified the C1R-associated changes. C1R also lowered HIF-1α levels by the proteasome-sensitive process accompanied by increased HIF-1α ubiquitination. Restoring HIF-1α expression counteracted the effects of C1R on FDX1, DLAT, DLST, invasion, and migration.
CONCLUSIONS
C1R is a shared cuproptosis-associated regulator in HBV infection and HCC. The data support a model in which C1R reduces aggressive phenotypes of HCC cells partly through destabilizing HIF-1α and reshaping copper-responsive processes.
Yehong Du, Junhua Li, Jing-Yi Jiang et al.· International Immunopharmaco...· 0 citations
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