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Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.

Glioblastoma (GBM) is the most common and deadly of the primary intracranial tumors and is comprised of subsets that show plasticity and marked heterogeneity, contributing to the lack of success in genomic profiling to guide development of precision medicine for these tumors. In this study, a mutation in isocitrate dehydrogenase 1 was found to suppress the transforming growth factor-beta signaling pathway and E2F4 interacted with Smad3 to inhibit expression of mesenchymal markers. However, palmitoylation of Smad3 mediated by palmitoyltransferase ZDHHC19 promoted activation of the transforming growth factor-beta signaling pathway, and its interaction with EP300 promoted expression of mesenchymal markers in the mesenchymal subtype of GBM. Smad3 and hypoxia-inducible factor 1-alpha may be important molecular targets for treatment of glioma because they appear to coordinate the basic aspects of cancer stem cell biology.

Background Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and is the leading cause of cancer death worldwide. Its progression is characterized by genomic instability. In turn, the level of genomic instability affects the prognosis and immune status of patients with LUAD. However, the impact of molecular features associated with genomic instability on the tumor microenvironment (TME) has not been well characterized. In addition, the effect of the genes related to genomic instability in LUAD on individualized treatment of LUAD is unknown. Methods The RNA-Sequencing, somatic mutation, and clinical data of LUAD patients were downloaded from publicly available databases. A genetic signature associated with genomic instability (GSAGI) was constructed by univariate Cox regression, Lasso regression, and multivariate Cox regression analysis. Bioinformatics analysis investigated the differences in prognosis, immune characteristics, and the most appropriate treatment strategy among different subtypes of LUAD patients. CCK-8 and colony formation verified the various effects of Etoposide on different subtypes of LUAD cell lines. Cell-to-cell communication analysis was performed using the “CellChat” R package. The expression of the risk factors in the GSAGI was verified using real-time quantitative PCR (qRT-PCR) and Immunohistochemistry (IHC). Results We constructed and validated the GSAGI, consisting of five genes: ANLN, RHOV, KRT6A, SIGLEC6, and KLRG2. The GSAGI was an independent prognostic factor for LUAD patients. Patients in the high-risk group distinguished by the GSAGI are more suitable for chemotherapy. More immune cells are infiltrating the tumor microenvironment of patients in the low-risk group, especially B cells. Low-risk group patients are more suitable for receiving immunotherapy. The single-cell level analysis confirmed the influence of the GSAGI on TME and revealed the Mode of action between tumor cells and other types of cells. qRT-PCR and IHC showed increased ANLN, RHOV, and KRT6A expression in the LUAD cells and tumor tissues. Conclusion This study confirms that genes related to genomic instability can affect the prognosis and immune status of LUAD patients. The GSAGI we identified has the potential to guide clinicians in predicting clinical outcomes, assessing immunological status, and even developing personalized treatment plans for LUAD patients.

Glioblastoma stem cells (GSCs) are a highly tumorigenic cell subgroup of glioblastoma (GBM). Glycogen synthase kinase 3β (GSK3β) is considered a key hub for promoting malignant phenotypes in GBM. However, the functional relationships between GSK3β and GSCs in GBM are unclear. Here, we found that GSK3β was noted as a substrate for ZDHHC4-mediated palmitoylation at the Cys14 residue, which enhanced GBM temozolomide (TMZ) resistance and GSC self-renewal. Clinically, the expression level of ZDHHC4 was upregulated in GBM, which significantly correlated with tumor grade and poor prognosis. The above phenotypes were based on decreasing p-Ser9 and increasing p-Tyr216 by GSK3β palmitoylation, which further activated the enhancer of the zeste homolog 2 (EZH2)–STAT3 pathway. Notably, STAT3 silencing also inhibited ZDHHC4 expression. This study revealed that GSK3β palmitoylation mediated by ZDHHC4 improved the stemness of TMZ-resistant GBM by activating the EZH2–STAT3 signaling axis, providing a new theoretical basis for further understanding the mechanism of TMZ resistance and recurrence after treatment.

Background Glioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear. Methods This study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches. Results ZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment. Conclusions Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.

Background A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. Methods The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. Results In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

DNA methylation is an important regulator of gene expression, and plays a significant role in carcinogenesis in the brain. Here, we explored specific prognosis-subtypes based on DNA methylation status using 138 Glioblastoma Multiforme (GBM) samples from The Cancer Genome Atlas (TCGA) database. The methylation profiles of 11,637 CpG sites that significantly correlated with survival in the training set were employed for consensus clustering. We identified three GBM molecular subtypes, and their survival curves were distinct from each other. Furthermore, ten feature CpG sites were obtained on conducting a weighted gene co-expression network analysis (WGCNA) of the CpG sites. We were able to classify the samples into high- and low-methylation groups, and classified the prognosis information of the samples after cluster analysis of the training set samples using the hierarchical clustering algorithm. Similar results were obtained in the test set and clinical GBM specimens. Finally, we found that a positive relationship existed between methylation level and sensitivity to temozolomide (or radiotherapy) or anti-migration ability of GBM cells. Taken together, these results suggest that the model constructed in this study could help explain the heterogeneity of previous molecular subgroups in GBM and can provide guidance to clinicians regarding the prognosis of GBM.

Long non-coding RNAs (lncRNAs) are tissue-specific expression patterns and dysregulated in cancer. How they are regulated still needs to be determined. We aimed to investigate the functions of glioma-specific lncRNA LIMD1-AS1 activated by super-enhancer (SE) and identify the potential mechanisms. In this paper, we identified a SE-driven lncRNA, LIMD1-AS1, which is expressed at significantly higher levels in glioma than in normal brain tissue. High LIMD1-AS1 levels were significantly associated with a shorter survival time of glioma patients. LIMD1-AS1 overexpression significantly enhanced glioma cells proliferation, colony formation, migration, and invasion, whereas LIMD1-AS1 knockdown inhibited their proliferation, colony formation, migration, and invasion, and the xenograft tumor growth of glioma cells in vivo. Mechanically, inhibition of CDK7 significantly attenuates MED1 recruitment to the super-enhancer of LIMD1-AS1 and then decreases the expression of LIMD1-AS1. Most importantly, LIMD1-AS1 could directly bind to HSPA5, leading to the activation of interferon signaling. Our findings support the idea that CDK7 mediated-epigenetically activation of LIMD1-AS1 plays a crucial role in glioma progression and provides a promising therapeutic approach for patients with glioma.

Background Long non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes glioma progression. Methods RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays, and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target. Results We identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc and EGR1/IL-6 signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells. Conclusions Our study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.