Cell Death and Differentiation最新文献

We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted Mir34a in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as Cdk8⁺ macrophages and Mrc1⁺, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2, and 32 predicted Mir34a target mRNAs. Furthermore, Mir34a-deficient BMDMs showed enhanced migration, elevated expression of Csf1r and a shift towards M2-like polarization when compared to Mir34a-proficient BMDMs. Concomitant deletion of Csf1r or treatment with a Csf1r inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid Mir34a in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as Csf1r. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.

Excessive fructose intake has been associated with the development and progression of pancreatic cancer. This study aimed to elucidate the relationship between fructose utilization and pancreatic cancer progression. Our findings revealed that pancreatic cancer cells have a high capacity to utilize fructose and are capable of converting glucose to fructose via the AKR1B1-mediated polyol pathway, in addition to uptake via the fructose transporter GLUT5. Fructose metabolism exacerbates pancreatic cancer proliferation by enhancing glycolysis and accelerating the production of key metabolites that regulate angiogenesis. However, pharmacological blockade of fructose metabolism has been shown to slow pancreatic cancer progression and synergistically enhance anti-tumor capabilities when combined with anti-angiogenic agents. Overall, targeting fructose metabolism may prove to be a promising therapeutic approach in the treatment of pancreatic cancer.

Fructose metabolism has emerged as a significant contributor to cancer cell proliferation, yet the underlying mechanisms and sources of fructose for cancer cells remain incompletely understood. In this study, we demonstrate that cancer cells can convert glucose into fructose through a process called the AKR1B1-mediated polyol pathway. Inhibiting the endogenous production of fructose through AKR1B1 deletion dramatically suppressed glycolysis, resulting in reduced cancer cell migration, inhibited growth, and the induction of apoptosis and cell cycle arrest. Conversely, the acceleration of endogenous fructose through AKR1B1 overexpression has been shown to significantly enhance cancer cell proliferation and migration with increased S cell cycle progression. Our findings highlight the crucial role of endogenous fructose in cancer cell malignancy and support the need for further investigation into AKR1B1 as a potential cancer therapeutic target.

Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.

BCL-2 family proteins regulate apoptosis by initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors BAX and BAK is controlled by the interplay of anti-apoptotic BCL-2 proteins (e.g., MCL-1) and pro-apoptotic BH3-only proteins (e.g., BIM). Using a genome-wide CRISPR-dCas9 transactivation screen we identified BNIP5 as an inhibitor of BAK-, but not BAX-induced apoptosis. BNIP5 blocked BAK activation in different cell types and in response to various cytotoxic therapies. The BH3 domain of BNIP5 was both necessary and sufficient to block BAK activation. Mechanistically, the BH3 domain of BNIP5 acts as a selective BAK activator, but a poor de-repressor of complexes between BAK and pro-survival BCL-2 family proteins. By promoting the binding of activated BAK to MCL-1 or BCL-xL, BNIP5 inhibits apoptosis when BAX is absent. Based on our observations, BNIP5 can act functionally as an anti-apoptotic BH3-only protein.

Lipid metabolism reprogram plays key roles in breast cancer tumorigenesis and immune escape. The underlying mechanism and potential regulator were barely investigated. We thus established an in vivo tumorigenesis model, mice-bearing breast cancer cells were treated with an ordinary diet and high-fat diet, species were collected and subjected to circRNA sequence to scan the potential circRNAs regulating the lipid metabolism. CircSpdyA was one of the most upregulated circRNAs and had the potential to encode a 127-aa micro peptide (referred to as 127aa). 127 aa promotes tumorigenesis through promoting the fatty acid de novo synthesis by directly binding to FASN. Single-cell sequence indicated 127aa inhibited NK cell infiltration and function. This was achieved by inhibiting the transcription of NK cell activators epigenetically. Moreover, lipid-laden from 127aa positive cancer cells transferred to NK cells inhibited the cytotoxicity. Taken together, circSpdyA encoded 127aa promotes fatty acid de novo synthesis through directly binding with FASN and induced NK cell repression by inhibiting the transcription of NK cell activators.

CD8⁺ T-cell responses are meticulously orchestrated processes regulated by intercellular receptor:ligand interactions. These interactions critically control the dynamics of CD8⁺ T-cell populations that is crucial to overcome threats such as viral infections or cancer. Yet, the mechanisms governing these dynamics remain incompletely elucidated. Here, we identified a hitherto unknown T-cell referred function of the self-ligating surface receptor SLAMF7 (CD319) on CD8⁺ T cells during initiation of cytotoxic T-cell responses. According to its cytotoxicity related expression on T effector cells, we found that CD8⁺ T cells could utilize SLAMF7 to transduce environmental cues into cellular interactions and information exchange. Indeed, SLAMF7 facilitated a dose-dependent formation of stable homotypic contacts that ultimately resulted in stable cell-contacts, quorum populations and commitment to expansion and differentiation. Using pull-down assays and network analyses, we identified novel SLAMF7-binding intracellular signaling molecules including the CRK, CRKL, and Nck adaptors, which are involved in T-cell contact formation and may mediate SLAMF7 functions in sensing and adhesion. Hence, providing SLAMF7 signals during antigen recognition of CD8⁺ T cells enhanced their overall magnitude, particularly in responses towards low-affinity antigens, resulting in a significant boost in their proliferation and cytotoxic capacity. Overall, we have identified and characterized a potent initiator of the cytotoxic T lymphocyte response program and revealed advanced mechanisms to improve CD8⁺ T-cell response decisions against weak viral or tumor-associated antigens, thereby strengthening our defense against such adversaries.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death initiated by oxidative stress and lipid peroxidation. Recent evidence has linked ferroptosis to the action of the transcription factor Nuclear factor erythroid-2 derived,-like-1 (NFE2L1). NFE2L1 regulates proteasome abundance in an adaptive fashion, maintaining protein quality control to secure cellular homeostasis, but the regulation of NFE2L1 during ferroptosis and the role of the ubiquitin-proteasome system (UPS) herein are still unclear. In the present study, using an unbiased proteomic approach charting the specific ubiquitylation sites, we show that induction of ferroptosis leads to recalibration of the UPS. RSL3-induced ferroptosis inhibits proteasome activity and leads to global hyperubiquitylation, which is linked to NFE2L1 activation. As NFE2L1 resides in the endoplasmic reticulum tethered to the membrane, it undergoes complex posttranslational modification steps to become active and induce the expression of proteasome subunit genes. We show that proteolytic cleavage of NFE2L1 by the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is a critical step for the ferroptosis-induced feed-back loop of proteasome function. Cells lacking DDI2 cannot activate NFE2L1 in response to RSL3 and show global hyperubiquitylation. Genetic or chemical induction of ferroptosis in cells with a disrupted DDI2-NFE2L1 pathway diminishes proteasomal activity and promotes cell death. Also, treating cells with the clinical drug nelfinavir, which inhibits DDI2, sensitized cells to ferroptosis. In conclusion, our results provide new insight into the importance of the UPS in ferroptosis and highlight the role of the DDI2-NFE2L1 as a potential therapeutic target. Manipulating DDI2-NFE2L1 activity through chemical inhibition might help sensitizing cells to ferroptosis, thus enhancing existing cancer therapies.

Glucose sensing and metabolic adaptation to glucose availability in the tumor microenvironment are critical for cancer development. Here we show that HKDC1, a hexokinase highly expressed in cancer associated with poor prognosis, functions as a glucose sensor that alters its stability in response to environmental glucose. The glucose-sensing domain is located between amino acids 751-917, with Ser896 as a key residue that regulates HKDC1 stability by affecting Lys620 ubiquitination. This sensing mechanism enables cellular adaptation to glucose starvation by promoting mitochondrial fatty acid utilization. Furthermore, HKDC1 promotes tumor growth by sequestering prohibitin 2 (PHB2) to disable its suppressive effect on SP1, thus promoting the expression of pro-oncogenic molecules. Abrogation of HKDC1 by genetic knockout or by glucose depletion releases PHB2, leading to suppression of cancer cell proliferation and inhibition of tumor growth. Our study reveals a previously unrecognized role of HKDC1 in glucose sensing and metabolic adaptation, and identifies HKDC1 as a potential therapeutic target.