Breast cancer is one of the most prevalent cancers worldwide. Recent studies have increasingly emphasized the role of oxidative stress in the initiation and progression of breast cancer. This article reviews how oxidative stress imbalance influences the occurrence and advancement of breast cancer, elucidating the intricate mechanisms through which reactive oxygen species (ROS) operate in this context and their potential therapeutic applications. By highlighting these critical insights, this review aims to enhance our understanding of oxidative stress as a potential target for innovative therapeutic strategies in the management of breast cancer.

Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. But underlying function and mechanism of fascin on tumorigenesis in melanoma remain elusive. The melanoma cell lines WM793 and WM39 were employed for the soft agar and sphere formation assay. Quantitative RT-PCR and Western blot were performed for identifying the gene expression at mRNA and protein levels, respectively. Co-IP and in vitro GST pulldown experiments were used to test the interaction between fascin and MST2. Fascin regulates tumorigenesis and cancer cell stemness in melanoma through inhibition of the Hippo pathway kinase MST2 and the activation of transcription factor TAZ. Our data showed that fascin interacts with the kinase domain of MST2 to inhibit its homodimer formation and kinase activity. Depletion of fascin led to increase of p-LATS level and decrease of TAZ, but not YAP. We also demonstrated that fascin regulates melanoma tumorigenesis independent of its actin-bundling activity. Fascin is a new regulator of the MST2-LATS-TAZ pathway and plays a critical role in melanoma tumorigenesis. Inhibition of fascin reduces melanoma tumorigenesis and stemness, and thus fascin could be a potential therapeutic target for this malignancy.

O-linked GlcNAc (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalk with phosphorylation and ubiquitination to orchestrate various biological processes. The mechanisms underlying the involvement of O-GlcNAc modifications in N⁶-methyladenosine (m⁶A) regulation are not fully characterized. Herein, we show that O-GlcNAc modifies the m⁶A mRNA reader YTH domain family 1 (YTHDF1) and fine-tunes its nuclear translocation by the exportin protein Crm1. First, we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified Ser196/Ser197/Ser198 as the YTHDF1 O-GlcNAcylation sites, as described in numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196A/S197F/S198A (AFA) mutant, which significantly attenuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 promotes the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT-YTHDF1-c-Myc axis underlies colorectal cancer tumorigenesis.

Objective: Stromal interaction molecule 1 (STIM1) overexpression has been reported to play an important role in progression ofseveral cancers. However, the mechanism of STIM1 overexpression and its relationship with hypoxia in pancreatic ductaladenocarcinoma (PDAC) remains unclear. Methods: STIM1 and HIF-1α expression was tested using immunohistochemistry in tissue microarray (TMA) includingpancreatic cancer and matched normal pancreatic tissues, and their relationships with clinicopathological parameters werestatistically analyzed. q-PCR, Western blot, ChIP, and luciferase assay were employed to 030 analyze transcriptional regulationbetween HIF-1α and STIM1 in pancreatic cancer PANC-1 cells. Results: Both STIM1 and HIF-1α showed higher positive rates and up-regulated expression in cancer tissues compared to that ofnormal tissues (P < 0.05). The Kaplan–Meier method revealed that higher HIF-1α and STIM1 expression levels were significantlycorrelated with decreased disease-free survival (P = 0.025 and P = 0.029, respectively). The expression of HIF-1α showed asignificant positive correlation with that of STIM1 in cancer tissues (rs = 0.3343, P = 0.0011) and pancreatic cancer cell lines.Furthermore, ChIP and luciferase assays confirmed that HIF-1α bound to the STIM1 promoter and regulated its expression inPANC-1 cells. Conclusions: In hypoxia microenvironment, up-regulated expression of STIM1 mediated by HIF-1α promotes PDACprogression. HIF-1α and STIM1 are potential prognostic markers and/or therapeutic targets for PDAC treatment.

Hepatocyte Nuclear Factor 4 Alpha (HNF4α) is a master transcription factor mainly expressed in the liver, kidney, intestine and endocrine pancreas. It regulates multiple target genes involved in embryonic development and metabolism. HNF4α-related diseases include non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and diabetes mellitus. Recently, HNF4α has been emerging as a key player in a variety of cancers. In this review, we summarized the role and mechanism of HNF4α in different types of cancers, especially in liver and colorectal cancer, aiming to provide additional guidance for intervention of these diseases.