Y-box binding protein 1 (YBX1), a member of the Cold Shock Domain protein family, is overexpressed in various human cancers and is recognized as an oncogenic gene associated with poor prognosis. YBX1’s functional diversity arises from its capacity to interact with a broad range of DNA and RNA molecules, implicating its involvement in diverse cellular processes. Independent investigations have unveiled specific facets of YBX1’s contribution to cancer development. This comprehensive review elucidates YBX1’s multifaceted role in cancer across cancer hallmarks, both in cancer cell itself and the tumor microenvironment. Based on this, we proposed YBX1 as a potential target for cancer treatment. Notably, ongoing clinical trials addressing YBX1 as a target in breast cancer and lung cancer have showcased its promise for cancer therapy. The ramp up in in vitro research on targeting YBX1 compounds also underscores its growing appeal. Moreover, the emerging role of YBX1 as a neural input is also proposed where the high level of YBX1 was strongly associated with nerve cancer and neurodegenerative diseases. This review also summarized the up-to-date advanced research on the involvement of YBX1 in pancreatic cancer.

Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell–mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1−/−;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage–induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN–mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer. Significance: NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a pivotal role in tumour progression and metastasis by induction epithelial-mesenchymal transition (EMT), with activation of stem cell traits, immune evasion and epigenetic reprogramming. However, the relationship between ZEB family members’ post-translational modification (PTM) and tumourigenesis remains largely unknown. Therefore, we focussed on the PTM of ZEBs and potential therapeutic approaches in cancer progression. This review provides an overview of the diverse functions of ZEBs in cancer and the mechanisms and therapeutic implications that target ZEB family members’ PTMs.

ARG2 has been reported to inhibit autophagy in vascular endothelial cells and keratinocytes. However, studies of its mechanism of action, its role in skin fibroblasts, and the possibility of promoting autophagy and inhibiting cellular senescence through ARG2 inhibition are lacking. We induced cellular senescence in dermal fibroblasts by using H₂O₂. H₂O₂-induced fibroblast senescence was inhibited upon ARG2 knockdown and promoted upon ARG2 overexpression. The microRNA miR-1299 suppressed ARG2 expression, thereby inhibiting fibroblast senescence, and miR-1299 inhibitors promoted dermal fibroblast senescence by upregulating ARG2. Using yeast two-hybrid assay, we found that ARG2 binds to ARL1. ARL1 knockdown inhibited autophagy and ARL1 overexpression promoted it. Resolvin D1 (RvD1) suppressed ARG2 expression and cellular senescence. These data indicate that ARG2 stimulates dermal fibroblast cell senescence by inhibiting autophagy after interacting with ARL1. In addition, RvD1 appears to promote autophagy and inhibit dermal fibroblast senescence by inhibiting ARG2 expression. Taken together, the miR-1299/ARG2/ARL1 axis emerges as a novel mechanism of the ARG2-induced inhibition of autophagy. Furthermore, these results indicate that miR-1299 and pro-resolving lipids, including RvD1, are likely involved in inhibiting cellular senescence by inducing autophagy.

Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for the treatment of edema caused by excessive body fluid. However, its clinical use is limited due to its low bioavailability and side effects, such as liver damage and hearing loss at high doses. Despite this, ECA has recently emerged as a potential anticancer agent through the approach of drug repositioning, with a novel mechanism of action. ECA has been shown to regulate cancer hallmark processes such as proliferation, apoptosis, migration and invasion, angiogenesis, inflammation, energy metabolism, and the increase of inhibitory growth factors through various mechanisms. Additionally, ECA has been used as a scaffold for synthesizing a new material, and various derivatives have been synthesized. This review explores the potential of ECA and its derivatives as anticancer agents, both alone and in combination with adjuvants, by examining their effects on ten hallmarks of cancer and neuronal contribution to cancer. Furthermore, we investigated the trend of synthesis research of a series of ECA derivatives to improve the bioavailability of ECA. This review highlights the importance of ECA research and its potential to provide a cost-effective alternative to new drug discovery and development for cancer treatment.

LW1497 suppresses the expression of the hypoxia-inducing factor (HIF)-1α inhibiting malate dehydrogenase. Although hypoxia and HIF-1α are known to be important in cancer, LW1497 has not been therapeutically applied to cancer yet. Thus, we investigated the effect of LW1497 on the epithelial-mesenchymal transition (EMT) of lung cancer cells. A549 and H1299 lung cancer cells were induced to undergo via TGF-β1 treatment, resulting in the downregulation of E-cadherin and upregulation of N-cadherin and Vimentin concurrently with increases in the migration and invasion capacities of the cells. These effects of TGF-β1 were suppressed upon co-treatment of the cells with LW1497. An RNA-seq analysis revealed that LW1497 induced differential expression of genes related to hypoxia, RNA splicing, angiogenesis, cell migration, and metastasis in the A549 lung cancer cell lines. We confirmed the differential expression of Slug, an EMT-related transcription factor. Results from Western blotting and RT-PCR confirmed that LW1497 inhibited the expression of EMT markers and Slug. After orthotopically transplanting A549 cancer cells into mice, LW1497 was administered to examine whether the lung cancer progression was inhibited. We observed that LW1497 reduced the area of cancer. In addition, the results from immunohistochemical analyses showed that LW1497 downregulated EMT markers and Slug. In conclusion, LW1497 suppresses cancer progression through the inhibition of EMT by downregulating Slug.