Biochimica et biophysica acta. Molecular cell research最新文献

Background

Methods

Results

Conclusion

Abnormal alternative splicing (AS) caused by dysregulated expression of splicing factors plays a crucial role in tumorigenesis and progression. The serine/arginine-rich (SR) RNA-binding protein family is a major class of splicing factors regulating AS. However, their roles and mechanisms in renal cell carcinoma (RCC) development and progression are not fully understood. Here, we found that SR splicing factor 3 (SRSF3) was an important splicing factor affecting RCC progression. SRSF3 was downregulated in RCC tissues and its low level was associated with decreased overall survival time of RCC patients. SRSF3 overexpression suppressed RCC cell malignancy. Mechanistically, the binding of SRSF3 to SP4 exon 3 led to the inclusion of SP4 exon 3 and the increase of long SP4 isoform (L-SP4) level in RCC cells. L-SP4, but not S-SP4 overexpression suppressed RCC cell malignancy. Meanwhile, L-SP4 participated in SRSF3-mediated anti-proliferation by transcriptionally promoting SMAD4 expression. Taken together, our findings provide new insights into the anticancer mechanism of SRSF3, suggesting that SRSF3 may serve as a novel potential therapeutic target for RCC.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide with a poor clinical prognosis. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an unidentified protein phosphatase 1 regulatory subunit that is associated with the occurrence and development of various cancers. Recently, PPP1R14B was found to contribute to paclitaxel resistance and cell progression in triple-negative breast cancer; however, the role of PPP1R14B in HCC is unknown. Here, we found that PPP1R14B was highly expressed in HCC tissues, which suggested a poor prognosis. Knockdown of PPP1R14B significantly inhibited the survival and tumorigenic ability of HCC cells, while overexpression of PPP1R14B had the opposite effects. Mechanistically, Ribosomal Protein S6 Kinase type 1(RPS6KA1) was identified as the target gene of PPP1R14B. PPP1R14B maintained the stability and phosphorylation of RPS6KA1, and positively regulated activation of the AKT/NF-κB pathway. Importantly, PPP1R14B-deficient tumor suppression could be partially restored by wild-type but not phosphorylated mutant RPS6KA1. Taken together, these findings shed light on the function and mechanism of PPP1R14B in HCC progression, indicating PPP1R14B is a promising molecular target for the treatment of HCC.

DNA double-strand breaks (DSBs) are considered one of the most harmful forms of DNA damage. These DSBs are repaired through non-homologous end joining (NHEJ) and homologous recombination (HR) pathways and defects in these processes can lead to genomic instability and promote tumorigenesis. Phosphatase and Tensin homolog (PTEN) are crucial in HR repair. However, its involvement in the NHEJ repair pathway has remained elusive. In this study, we investigate the function of epigenetic regulation of PTEN in the NHEJ repair pathway. Our findings indicate that both the phosphorylation and phosphatase activity of PTEN are required for efficient NHEJ-mediated DSB repair. During the DNA damage response, we observed a reduced expression and chromatin attachment of the key NHEJ proteins, including Ku70/80, DNA-PKcs, XRCC4, and XLF, in PTEN-null cells. This reduction was attributed to the instability of these NHEJ proteins, as confirmed by our protein half-life assay. We have demonstrated that the DNA-PKcs inhibitor, NU7026, suppresses the DNA damage-induced phosphorylation of the C-terminal of PTEN. Thus, our study indicates that PTEN could be a target of DNA-PKcs. Protein-protein docking analysis also shows that PTEN interacts with the C-terminal region of DNA-PKcs. PTEN null cells exhibit compromised DNA-PKcs foci after DNA damage as it is in a hyper-phosphorylated state. Phospho-PTEN assists in recruiting DNA-PKcs on the DNA damage site by maintaining its hypo-phosphorylated state which also depends on its phosphatase activity. Therefore, after DNA damage, crosstalk between PTEN and DNA-PKcs modulates the NHEJ pathway. Thus, during DNA damage, PTEN gets phosphorylated directly or indirectly by DNA-PKcs and attaches to chromatin, resulting in the dephosphorylation of DNA-PKcs and subsequently recruitment of other NHEJ factors on chromatin occurs for efficient execution of the NHEJ pathway. Thus, our research provides a molecular understanding of the epigenetic regulation of PTEN and its significant role in controlling the NHEJ pathway.

Nuclear speckles, also known as interchromatin granule clusters (IGCs), are subnuclear domains highly enriched in proteins involved in transcription and mRNA metabolism and, until recently, have been regarded primarily as their storage and modification hubs. However, several recent studies on non-neuronal cell types indicate that nuclear speckles may directly contribute to gene expression as some of the active genes have been shown to associate with these structures.

Neuronal activity is one of the key transcriptional regulators and may lead to the rearrangement of some nuclear bodies. Notably, the impact of neuronal activation on IGC/nuclear speckles organization and function remains unexplored. To address this research gap, we examined whether and how neuronal stimulation affects the organization of these bodies in granular neurons from the rat hippocampal formation. Our findings demonstrate that neuronal stimulation induces morphological and proteomic remodelling of the nuclear speckles under both in vitro and in vivo conditions. Importantly, these changes are not associated with cellular stress or cell death but are dependent on transcription and splicing.

In nature, the majority of known RNA-protein interactions are transient. Our recent study has depicted a novel mechanism known as RNAylation, which covalently links proteins and RNAs. This novel modification bridges the realms of RNA and protein modifications. This review specifically explores RNAylation catalyzed by bacteriophage T4 ADP-ribosyltransferase ModB, with a focus on its protein targets and RNA substrates in the context of Escherichia coli-bacteriophage T4 interaction. Additionally, we discuss the biological significance of RNAylation and present perspectives on RNAylation as a versatile bioconjugation strategy for RNAs and proteins.

Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/β-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC.

High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect (P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6K^Thr389. Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.

The nucleotide oligomerization domain (NOD)-like receptors containing pyrin (NLRP) family of cytosolic pattern-recognition receptors play an integral role in host defense following exposure to a diverse set of pathogenic and sterile threats. The canonical event following ligand recognition is the formation of a heterooligomeric signaling complex termed the inflammasome that produces pro-inflammatory cytokines. Dysregulation of this process is associated with many autoimmune, cardiovascular, metabolic, and neurodegenerative diseases. Despite the range of activating stimuli which affect varied cell types, recent literature makes evident that reactive oxygen species (ROS) are integral to the initiation and propagation of inflammasome signaling. Notably, ROS production and inflammasome activation act in a positive feedback loop to promote this potent immune response. While NLRP3 is by far the most extensively studied NLRP, there is also sufficient literature to make these conclusions for other NLRPs family members. In all cases, a knowledge gap exists regarding the molecular targets and effects of ROS. Future research to define these targets and to parse the order and timing of ROS-mediated NLRP activation will provide meaningful insights into inflammasome biology. This will create novel therapeutic opportunities for the numerous illnesses that are impacted by inflammasome activity.

Proteostasis, including protein folding mediated by molecular chaperones, protein degradation, and stress response pathways in organelles like ER (unfolded protein response: UPR), are responsible for cellular protein quality control. This is essential for cell survival as it regulates and reprograms cellular processes. Here, we underscore the role of the proteostasis pathway in Apicomplexan parasites with respect to their well-characterized roles as well as potential roles in many parasite functions, including survival, multiplication, persistence, and emerging drug resistance. In addition to the diverse physiological importance of proteostasis in Apicomplexa, we assess the potential of the pathway's components as chemotherapeutic targets.