Non-canonical function of PHGDH promotes HCC metastasis by interacting with METTL3
程彬 等
Abstract
Purpose: Phosphoglycerate dehydrogenase (PHGDH), a pivotal enzyme in serine synthesis, plays a key role in the malignant progression of tumors through both its metabolic activity and moonlight functions. This study aims to elucidate the non-canonical function of PHGDH in promoting hepatocellular carcinoma (HCC) metastasis through its interaction with methyltransferase-like 3 (METTL3), potentially uncovering a novel therapeutic target.
Methods: Western blot was used to study PHGDH expression changes under anoikis and cellular functional assays were employed to assess its role in HCC metastasis. PHGDH-METTL3 interactions were explored using GST pull-down, Co-immunoprecipitation and immunofluorescence assays. Protein stability and ubiquitination assays were performed to understand PHGDH’s impact on METTL3. Flow cytometry, cellular assays and nude mice model were used to confirm PHGDH's effects on anoikis resistance and HCC metastasis in vitro and in vivo.
Results: PHGDH is upregulated under anoikis conditions, thereby enhancing the metastatic potential of HCC cells. By interacting with METTL3, PHGDH prevents its ubiquitin-dependent degradation, resulting in higher METTL3 protein levels. This interaction upregulates epithelial-mesenchymal transition related genes, contributing to anoikis resistance and HCC metastasis. Nude mice model confirms that PHGDH’s interaction with METTL3 is crucial for driving HCC metastasis.
Conclusion: Our research presents the first evidence that PHGDH promotes HCC metastasis by interacting with METTL3. The PHGDH-METTL3 axis may serve as a potential clinical therapeutic target, offering new insights into the multifaceted roles of PHGDH in HCC metastasis.
full text: https://doi.org/10.1007/s13402-024-01029-2
SLC27A5 inhibits cancer stem cells by inducing alternative polyadenylation of METTL14 in hepatocellular carcinoma
唐鑫 等
Abstract
Solute carrier family 27 member 5 (SLC27A5/FATP5) is a liver-specific metabolic enzyme that plays a crucial role in fatty acid transport and bile acid metabolism. Deficiency of SLC27A5 promotes the progression of hepatocellular carcinoma (HCC) and is strongly associated with a poor prognosis. SLC27A5 exhibits noncanonical functions beyond its metabolic role; however, its specific mechanisms in hepatocarcinogenesis remain elusive and are therefore investigated in this study. Immunoprecipitation-mass spectrometry analysis showed that SLC27A5-interacting proteins were significantly enriched in alternative polyadenylation (APA). RNA-sequencing data provided evidence that SLC27A5 plays a global role in regulating APA events in HCC. Mechanistically, SLC27A5 facilitates the usage of the proximal polyadenylation site of METTL14 by downregulating the expression of the APA-associated factor PABPC1, resulting in the shortening of the METTL14-3′UTR and the conversion of METTL14-UL to METTL14-US. In contrast to METTL14-UL, METTL14-US escapes the inhibitory effect of miRNA targeting, leading to increased METTL14 expression. METTL14-US upregulation by SLC27A5 suppressed the stemness of HCC. Therefore, low levels of SLC27A5 and METTL14 may serve as reliable biomarkers for identifying poor prognosis in patients with HCC. In conclusion, SLC27A5/PABPC1 inhibits HCC stemness via APA-regulated expression of METTL14, providing potential avenues for the development of novel therapeutic strategies.
full text: https://doi.org/10.1016/j.gendis.2024.101488
Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A
陶俊吉 等
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality globally, with hypoxia recognized as a key factor in its progression. Solute carrier family 27 member 5 (SLC27A5/FATP5), a pivotal enzyme in hepatic fatty acid transport and bile acid metabolism, is frequently downregulated in hepatocellular carcinoma, resulting in poor prognosis. However, the link between hypoxia and the suppression of SLC27A5 in HCC remains to be elucidated. Here, we investigated the hypoxia-induced downregulation of SLC27A5 and its impact on HCC proliferation via the repression of hepatocyte nuclear factor 4 alpha (HNF4A). Utilizing in vitro and in vivo hepatocellular carcinoma models, we have demonstrated that hypoxic conditions significantly reduce SLC27A5 transcription, which is mediated by the suppression of HNF4A. This reduction leads to the activation of the AKT pathway and an increase in cyclin-dependent kinase 2 (CDK2) and Cyclin E1 (CCNE1) expression, promoting the transition from the G1 to S phase of the cell cycle and driving HCC proliferation. Furthermore, we show that the pharmacological activation of HNF4A using Benfluorex, in combination with the AKT inhibitor MK2206, significantly inhibits tumor growth in a subcutaneous MHCC-97H xenograft model, suggesting a synergistic therapeutic potential. Together, our study provides novel insights into the hypoxia-mediated regulatory mechanisms in HCC and highlights the HNF4A/SLC27A5/AKT axis as a promising target for combination therapy.
full text: https://doi.org/10.1016/j.bbamcr.2025.119916
