Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness.

Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.

Generation, secretion and degradation of cancer immunotherapy target PD-L1.

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.

LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer.

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. METHODS: Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). RESULTS: Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. CONCLUSION: LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Decoding CLU (Clusterin): Conquering cancer treatment resistance and immunological barriers.

One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms. CLU (Clusterin), a chaperone protein, has gained notoriety for its role in promoting resistance to a wide range of cancer treatments, including chemotherapy, radiation therapy, and targeted therapy. The protein has also been discovered to have a role in regulating the immunosuppressive environment within tumors. Its ability to influence oncogenic signaling and inhibit cell death bolster cancer cells resistant against treatments, which poses a significant challenge in the field of oncology. Researchers are actively investigating to the mechanisms by which CLU exerts its resistance-promoting effects, with the ultimate goal of developing strategies to circumvent its impact and enhance the effectiveness of cancer therapies. By exploring CLU's impact on cancer, resistance mechanisms, tumor microenvironment (TME), and therapeutic strategies, this review aims to contribute to the ongoing efforts to improve cancer treatment outcomes.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.

Identification of the upstream regulators of KDM5B in gastric cancer.

AIMS: Lysine-specific demethylase 5B (KDM5B) is an epigenetic regulator of chromatin that catalyzes the demethylation of histone 3 lysine 4. It is overexpressed in multiple cancer types and acts as a therapeutic target in cancer therapy. Nevertheless, its upstream regulatory pathway is not completely understood, prompting the search for the underlying biological factors driving KDM5B overexpression. MATERIALS AND METHODS: A comprehensive analysis was performed to examine the association between KDM5B overexpression and copy number variation (CNV), somatic mutation, mRNA expression, miRNA expression, and clinical characters from The Cancer Genome Atlas database. Coexpression and function enrichment analyses were performed with KDM5B-coexpressed genes. The gastric cancer (GC) cell line MKN45 was utilized to verify the regulation of KDM5B using the transcription factor (TF) Yin Yang 1 (YY1) and miR-29a-3p. KEY FINDINGS: KDM5B was overexpressed and associated with poor prognosis in GC. KDM5B upregulation was driven by CNV amplification and DNA hypomethylation rather than by KDM5B mutations. Enrichment analysis revealed that KDM5B-coexpressed genes were primarily related to the transmembrane transport function and the ubiquitin-mediated proteolysis signaling pathway. As a TF, YY1 might bind to the KDM5B promoter region to regulate KDM5B expression. In addition, miR-29a-3p might bind to and negatively regulate KDM5B expression. SIGNIFICANCE: Our results demonstrate that KDM5B expression is regulated via CNV amplification, DNA hypomethylation, and YY1 and miR-29a-3p; KDM5B expression regulation is associated with patient survival and tumor cell proliferation.

Lysine demethylase 5B (KDM5B): A potential anti-cancer drug target.

Lysine demethylase 5B (KDM5B) is a histone demethylase identified in 2007, which is responsible for erasing H3K4me2/3 activation marker. It participates in multiple repressive transcriptional complexes around target gene promoters and performs wide regulatory effects on chromatin structure. Until now, there is growing evidence for the oncogenic function of KDM5B. As the H3K4me2/3 residue represents the transcription initiation site of the active transcription gene, and demethylation of H3K4 is associated with transcriptional repression, making it a potential participant in inhibiting the expression of tumor suppressors. Therefore, KDM5B is considered as a promising drug target for cancer therapy, and many medicinal chemists are trying to design and synthesize potent and selective KDM5B inhibitors with the aid of high-throughput screening, structure based drug design, and structure activity relationship studies. This review focuses on the basic biochemical and physiological function of KDM5B and its involved mechanisms in cancers, a comprehensive overview of KDM5B inhibitors is also introduced.