image: (A) Proteins interacting with SLC27A5 were detected by IP-MS. APA-related RBPs (PMID: 22502866) and core cleavage/polyadenylation factors and associated RBP (PMID: 25906188) are illustrated in a Venn diagram. (B) Co-immunoprecipitation (Co-IP) of SLC27A5-Flag and PABPC1-HA using an anti-HA antibody (left) or an anti-Flag antibody (right) in HEK-293 cells. (C) Immunoblot analysis of Co-IP by anti-SLC27A5 and anti-PABPC1 in SNU449 cells (left) and HepG2 cells (right). (D) GST pull-down assays of the interaction between SLC27A5 and PABPC1. (E) Immunofluorescence staining to assess the subcellular co-localization of SLC27A5 and PABPC1 in HepG2 cells (scale bar: 20 μm). (F) Immunofluorescence staining was performed using an anti-Flag and anti-HA antibody in PLC/PRF/5 cells transfected with SLC27A5-Flag and PABPC1-HA to detect the subcellular co-localization of SLC27A5 and PABPC1 (scale bar: 20 μm). (G, H) Schematic representation of the SLC27A5 (G) and PABPC1 (H) deletion mutants, and Co-IP assays with the full-length PABPC1 and SLC27A5, respectively. The SLC27A5 deletion mutants covered amino acids 1–77 (ΔC) or 78–690 (ΔN). The PABPC1 deletion mutants covered amino acids 1–370 (ΔC) or 371–636 (ΔN).
Credit: Genes & Diseases
Hepatocellular carcinoma (HCC) is a common malignant tumor and the third leading cause of cancer-related mortality. The lack of effective treatment strategies may be attributed to tumor recurrence and metastasis. Liver cancer stem cells (LSCs) in the tumor tissues are known to drive HCC initiation, metastasis, and recurrence, and eliminating these cells may offer a promising avenue for improving the outcomes of anti-HCC therapies. Therefore, understanding the molecular mechanisms regulating liver cancer stem cell maintenance is essential to develop novel targeted therapeutic strategies.
In a recent study published in the Genes & Diseases journal, researchers at Chongqing Medical University provide mechanistic insights into the role of SLC27A5 in regulating liver cancer stemness.
The solute carrier family 27 member 5 (SLC27A5) is a fatty acid transport protein expressed exclusively in the liver and its deficiency is associated with hepatic fibrosis and HCC progression. Alternative polyadenylation (APA) is an important post-transcriptional gene-regulatory mechanism that generates mRNA isoforms with different 3′-untranslated regions (3′-UTRs). Aberrant APA events occur in various types of cancer, including HCC. In their previous study, the authors identified SLC27A5 as being involved in RNA-related processes, including alternative polyadenylation.
Using a combined screening process involving immunoprecipitation-mass spectrometry (IP-MS) of SLC27A5, APA core factors and related RBPs, and APA-associated RBPs, the authors identified, “an effective interaction between SLC27A5 and PABPC1”. PABPC1 is a nuclear-cytoplasmic shuttling protein involved in regulating 3′UTR-APA. It is highly expressed in various tumor tissues and is strongly associated with an unfavorable prognosis, particularly in HCC. This study showed that SLC27A5 facilitates the ubiquitinated degradation of PABPC1 through RBBP7, resulting in the downregulation of PABPC1.
Further experiments revealed that SLC27A5, through downregulating PABPC1 expression, reduces the utilization frequency of METTL14-dPAS, leading to a shift from METTL14 transcripts with longer 3'UTRs (METTL14-UL) to METTL14 transcripts with shorter 3'UTRs (METTL14-US), independent of its enzymatic activity.
Bioinformatics analysis indicated a negative correlation between METTL14 and the regulation of liver cancer stemness and between METTL14 mRNA levels and the expression of different HCC LCSC surface markers, suggesting a potential role of different METTL14 isoforms in the regulation of HCC stemness. In vitro and in vivo experiments demonstrated that i) METTL14-US effectively inhibits the stemness of HCC cells, ii) SLC27A5 inhibits HCC stemness by upregulating METTL14-US expression levels, independent of its enzyme activity, iii) SLC27A5/PABPC1 regulates METTL14 expression via the conversion of METTL14-UL/S, and iv) METTL14-US mRNA evades miRNA-mediated silencing, resulting in the upregulation of METTL14.
Further analysis of human HCC specimens showed that SLC27A5 deficiency upregulates the expression of PABPC1 and short 3'UTR isoforms of METTL14, inhibiting METTL14 expression and resulting in enhanced tumor progression.
In conclusion, "The discovery of the SLC27A5-PABPC1-METTL14 axis deepens our understanding of the metabolic network of cancer and mRNA alternative polyadenylation". The authors further suggest that "targeting SLC27A5-induced APA or METTL14-US may be a novel therapeutic approach for impeding HCC progression".
Reference
Title of the original paper: SLC27A5 inhibits cancer stem cells by inducing alternative polyadenylation of METTL14 in hepatocellular carcinoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101488
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