Cell Death & Disease最新文献

Cleft palate (CP) is a common congenital craniofacial malformation, which is caused by a combination of genetic and environmental factors. However, its underlying mechanism has not been elucidated. Sirtuin6 (SIRT6) mutation has been associated with craniofacial anomalies in humans. This study further defined the role of Sirt6 in palatogenesis by investigating the specific inactivation of Sirt6 in Wnt1-expressing cell lineages. Here, we demonstrated that Sirt6 conditioned knockout (Sirt6 cKO) could inhibit the osteogenesis of the palate which facilitated the occurrence of CP. Specifically, Sirt6 deficiency promoted the expression of glutamine oxaloacetic transaminase 1 (Got1) and glycolysis through deacetylation inhibition, which increased the proliferation of mouse embryonic palatal mesenchyme (MEPM) cells through the GOT1-lactate dehydrogenase A (LDHA)-transforming growth factor beta receptor 1 (TGFBR1) pathway in the early stage and inhibited the osteogenic differentiation of MEPM cells through the GOT1-LDHA-bone morphogenetic protein 2 (BMP2) pathway in the late stage. Notably, if there was a disturbance of the environment, such as retinoic acid (RA), the occurrence of CP increased. Also, the enhanced acetylation of histone 3 lysine 9 (H3K9) in Got1 induced by Sirt6 deficiency was mediated by the acetylase tat-interacting protein 60 (TIP60) rather than acetyltransferase p300 (P300). Additionally, inhibition of Got1 partially saved the promoting effect of Sirt6 cKO on the CP. Our study reveals the role of Sirt6 in facilitating CP, with Got1 as the primary driver.

Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation and ferroptosis remains unclear. In present study, we found that the acetylation of acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its protein stability and a double-edged sword regulation in nasopharyngeal carcinoma (NPC). On the one hand, ACSL4 could promote the malignant progress of tumors; on the other hand, it enhanced radiosensitivity by endowing NPC cells with ferroptosis-sensitive properties in vitro and in vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes the acetylation of ACSL4 at lysine 383, and deacetylase sirtuin 3 (SIRT3) mediates the deacetylation of ACSL4. Meanwhile, another deacetylase histone deacetylase 2 (HDAC2) enhances ACSL4 acetylation through inhibiting the transcription of SIRT3. Acetylation of ACSL4 inhibits F-box protein 10 (FBXO10)-mediated K48-linked ubiquitination, resulting in enhanced protein stability of ACSL4. This study reveals the novel regulatory mechanism of ferroptosis-related protein from the perspective of protein acetylation, and provides a novel method for the radiosensitivity of NPC.

Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.

Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.

The tumor microenvironment (TME) plays an important role in tumorigenesis and development. Tumor-associated macrophages (TAMs) are essential members of the TME, the exosomes and miRNAs they secrete are crucial in tumor regulation. Our previous study showed that GRP78-induced macrophages infinitely tend to be M2-type TAMs. In this study, the exosomes of M0 and GRP78-induced macrophage were collected and co-incubated with colorectal cancer (CRC) cells. The results implied that macrophage exosomes induced by GRP78 (GRP78-exos) significantly promoted stemness and chemoresistance in CRC in vitro and in vivo. Further, the top 5 miRNAs upregulated in GRP78-exos were obtained from miRNA sequencing data. The qRT-PCR validation revealed that miR-769-5p was the most observably upregulated and could be directly transferred into CRC cells via GRP78-exos. Mechanistically, the study indicated that miR-769-5p targeted MAPK1 to regulate the cell cycle-related proteins RB1, cyclin D1, and cyclin E1. This contributes to CRC cells entering a quiescent state, which leads to the development of chemoresistance. Moreover, miR-769-5p is also expressed higher in the tissues of 5-FU-resistant CRC patients. In summary, the findings indicate a novel function of miR-769-5p as a potential marker for the diagnosis and treatment of chemotherapy resistance in CRC.

Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon γ, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratification and prediction performance in the clinic.

Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, the upstream trigger of TBI-induced neuronal loss and the underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated in Alzheimer's disease and ischemic stroke and to play a role in cellular apoptosis, while its pathological significance in TBI has not been reported. Herein, we discovered for the first time that ZIPK expression was markedly elevated in neurons after TBI and that ZIPK caused massive neuronal apoptosis in peri-contusional brain regions. Zipk haploinsufficiency antagonized neuronal cell death and reversed several typical neuropathological changes induced by TBI. Mechanistically, we found that ZIPK affected neuronal viability by modulating death effector domain-containing DNA binding protein (DEDD) and caspase-3 pathway. Specifically, ZIPK could bind to and phosphorylate DEDD at the S9 residue, thus enhancing the stability of DEDD, and leading to the activation of caspase-3-mediated apoptotic cascade in neurons. The rescue of neuronal loss by ZIPK downregulation effectively alleviated TBI-induced behavioral deficits by preserving motor and cognitive abilities in vivo, supporting the decisive role of ZIPK dysregulation in TBI-associated neuronal dysfunctions by modulating neuronal survival. Furthermore, pharmacological suppression of ZIPK activity by a specific inhibitor prior to TBI protected neurons from brain injury-induced cell death and neuronal degeneration in vitro and in vivo by preventing DEDD upregulation and caspase-3 activation. In conclusion, our data reveal the essential contribution of ZIPK to TBI-induced neuronal cell death through the DEDD/caspase-3 cascade, and suggest the potential of targeting ZIPK as an effective strategy for treating TBI-related neuropathologies.

Mitochondrial damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA), TFAM (transcription factor A, mitochondrial), and ATP, which play crucial roles in the regulation of inflammatory environment in human diseases. However, the role of mitochondrial DAMPs in regulating tumor microenvironment (TME) remains unclear. Herein, we demonstrate that infiltration of M2-type tumor-associated macrophages (TAMs) was correlated with the resistance of hepatocellular carcinoma (HCC) to sorafenib. We found that cell-free mtDNA in the plasma was significantly increased in sorafenib-resistant HCC mice. Sorafenib induced mitochondrial dysfunction and promoted the release of mtDNA into extracellular matrix of HCC. Macrophages retook the mtDNA in the TME of HCC, activated TLR9 signaling, and promoted the activation of NF-κB and the polarization of TAMs into M2. Application of DNase I to digest mtDNA or depletion of macrophages with clodronate liposomes reduced M2 macrophage infiltration, decreased the growth of HCC, and sensitized the tumors to sorafenib. Furthermore, we showed that blocking the activation of TLR9 enhanced the therapeutic effect of sorafenib in HCC. Together, we demonstrate that sorafenib treatment leads to the release of mtDNA into TME in HCC, which in turn facilitates the polarization of TAMs into M2 macrophages through TLR9 activation and aggravates the resistance of HCC to sorafenib. Our study reveals a novel mechanism underlying circulating mtDAMPs in remodeling the HCC microenvironment by reprograming the TAMs and provides a new strategy for improving the therapeutic effect of sorafenib and overcoming its resistance in HCC.

The Warburg effect, also known as aerobic glycolysis, plays a crucial role in the onset and progression of colorectal cancer (CRC), although its mechanism remains unclear. In this study, bioinformatics analysis of public databases combined with validation using clinical specimens identified the transcription factor ONECUT3 as a key regulator related to the Warburg effect in CRC. Functionally, silencing ONECUT3 reverses the Warburg effect and suppresses tumor growth. Importantly, ONECUT3 promotes tumor growth in a glycolysis-dependent manner through hypoxia-inducible factor 1α (HIF-1α). Mechanistically, ONECUT3 does not directly regulate the expression of HIF-1α but instead inhibits its acetylation via histone deacetylase 6 (HDAC6). This deacetylation enhances the transcriptional activity of HIF-1α, ultimately upregulating multiple glycolysis-related genes downstream of HIF-1α, thereby driving the Warburg effect and facilitating tumor growth in CRC. These findings reveal a novel mechanism by which ONECUT3 regulates the Warburg effect in CRC and suggest that targeting ONECUT3 may offer a promising therapeutic strategy for CRC.