Fengrui Wu

Deubiquitinase OTUD4 Stabilizes SLC5A2 to Promote Pancreatic Cancer Proliferation and Migration Through Enchaining Glycolysis‐Mediated Autophagy

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its insidious onset, rapid progression, and poor treatment outcomes. Sodium glucose transporter 2 (SLC5A2) is the predominant sodium‐glucose transporter. Our study reveals that SLC5A2 interacted with ovarian tumor family deubiquitinase 4 (OTUD4) to stabilize and increase its expression in PDAC. SLC5A2 overexpression promoted pancreatic cancer cell proliferation in vitro and in vivo, while also promoting cell migration, invasion, and autophagy. Conversely, SLC5A2 knockdown reversed these effects. RNA‐seq and GSEA revealed that glycolysis pathway activation was inhibited following SLC5A2 knockdown. Consistent with this, qRT‐PCR and western blot analyses indicated reduced glycolysis‐related gene expression levels. Metabolomics further revealed that knockdown of SLC5A2 decreased intermediate product levels in glycolysis, as well as glucose intake. Glycolysis inhibitor (2‐DG) amplified the effect of SLC5A2 knockdown in promoting autophagy, resulting in decreased pancreatic cancer proliferation, migration, and invasion. Notably, the antitumor effects of SLC5A2 knockdown were reversed by Bafilomycin A1. Additionally, treatment with the SLC5A2 inhibitor, canagliflozin (CANA), inhibited pancreatic cancer growth by inhibiting glycolysis and enhancing autophagy in vitro/vivo. These findings suggest that SLC5A2 promotes pancreatic cancer progression by regulating the glycolysis‐autophagy axis, suggesting it as a therapeutic target for improving PDAC treatment outcomes.

CircRNF144B/miR-342-3p/FBXL11 axis reduced autophagy and promoted the progression of ovarian cancer by increasing the ubiquitination of Beclin-1

AbstractCircular RNAs (circRNAs) can regulate autophagy and ovarian cancer (OC) progression. However, autophagy-associated circRNAs involved in OC progression are largely unknown. Bioinformatics, RNA sequencing, and qRT-PCR were conducted to detect circRNF144B expression in OC as well as its relationship with patient prognosis. Functional experiments were used to determine the effects of circRNF144B on the proliferation, mobility and autophagy of OC. Double luciferase reporter assays, immunoprecipitation, and ubiquitination detection were performed to determine the molecular mechanisms of circRNF144B in autophagy and OC progression. CircRNF144B was elevated in OC tissues with low autophagy levels, and associated with poor prognosis. CircRNF144B promoted the malignant biological properties of OC cells, and inhibited the autophagy. Mechanistically, circRNF144B acts as a sponge for miR-342-3p and inhibits miR-342-3p-induced degradation of lysine demethylase 2 A (FBXL11) mRNA, leading to elevated FBXL11 protein levels. Elevated FBXL11 promoted the ubiquitination and degradation of Beclin-1, thus inhibiting autophagy. In conclusion, CircRNF144B increased FBXL11 level by sponging miR-342-3p, whereas elevated FBXL11 promoted the ubiquitination and protein degradation of Beclin-1, thus suppressing autophagy flux and promoting OC progression. Thus, circRNF144B may be an effective target for OC therapy.

Bisphenol A Promotes Ovarian Cancer Proliferation and Migration through the HK2/H3K18la/IGF2BP3 Sequential Regulatory Axis

Bisphenol A (BPA), an endocrine-disrupting chemical with estrogenic activity, has been implicated in cancer development, although its role remains controversial. This study investigated the effects of BPA on ovarian cancer and its underlying mechanisms. BPA treatment dose-dependently (0-10 μM) increased cell viability and invasion. Kyoto Encyclopedia of Genes and Genomes analysis revealed the enrichment of the central carbon metabolism pathway following BPA exposure. Consistent with this, BPA upregulated glycolytic enzymes HK2 and LDHA. In addition, BPA activated ERα, which enhanced HK2 transcription and promoted glycolysis. The resulting lactate accumulation increased histone H3 lysine 18 lactylation (H3K18la), enriched at the IGF2BP3 promoter, to upregulate its expression. IGF2BP3 then stabilized HK2 mRNA via m6A recognition, amplifying the glycolysis. Our findings suggest that BPA promotes ovarian cancer progression through the HK2/H3K18la/IGF2BP3 sequential regulatory axis, providing insights for epigenetic-targeted therapies.