Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by ...clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.
Ubiquitin-specific peptidase 10 (USP10) stabilizes both tumor suppressors and oncogenes in a context-dependent manner. However, the nature of USP10's role in non-small cell lung cancer (NSCLC) ...remains unclear. By analyzing The Cancer Genome Atlas (TCGA) database, we have shown that high levels of USP10 are associated with poor overall survival in NSCLC with mutant p53, but not with wild-type p53. Consistently, genetic depletion or pharmacological inhibition of USP10 dramatically reduces the growth of lung cancer xenografts lacking wild-type p53 and sensitizes them to cisplatin. Mechanistically, USP10 interacts with, deubiquitinates, and stabilizes oncogenic protein histone deacetylase 6 (HDAC6). Furthermore, reintroducing either USP10 or HDAC6 into a USP10-knockdown NSCLC H1299 cell line with null-p53 renders cisplatin resistance. This result suggests the existence of a "USP10-HDAC6-cisplatin resistance" axis. Clinically, we have found a positive correlation between USP10 and HDAC6 expression in a cohort of NSCLC patient samples. Moreover, we have shown that high levels of USP10 mRNA correlate with poor overall survival in a cohort of advanced NSCLC patients who received platinum-based chemotherapy. Overall, our studies suggest that USP10 could be a potential biomarker for predicting patient response to platinum, and that targeting USP10 could sensitize lung cancer patients lacking wild-type p53 to platinum-based therapy.
Tumor repopulation during therapy is an important cause of treatment failure. Strategies to overcome repopulation are arising in parallel with advances in the comprehension of underlying biological ...mechanisms. Here, we reveal a new mechanism by which high mobility group box 1 (HMGB1) released by dying cells during radiotherapy or chemotherapy could stimulate living tumor cell proliferationInhibition or genetic ablation of HMGB1 suppressed tumor cell proliferation. This effect was due to binding of HMGB1with the member receptor for advanced glycation end-products (RAGE), which activated downstream ERK and p38 signaling pathway and promoted cell proliferation. Furthermore, higher HMGB1 expression in tumor tissue correlated with poor overall survival and higher HMGB1 concentration was detected in serum of patients who accepted radiotherapy. Collectively, the results from this study suggested that interaction between dead cells and surviving cells might influence the fate of tumor. HMGB1 could be a novel tumor promoter with therapeutic and prognostic relevance in cancers.
The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with ...node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m
A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m
A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m
A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.
As the most promising biomass material, bamboo has been widely used, but at the same time, it is subject to many problems, such as processing residues and the failure of high-value utilization of ...residues. In this paper, bamboo powder and polybutylene succinate (PBS) were used as the main raw materials, and by changing the ratio of bamboo powder to PBS and adding polypropylene (PP) or polyethylene (PE) in combination with PBS, the effects of the ratio, as well as the effects of the use of PP and PE, on the physical–mechanical, thermal, and degradation properties of bamboo–plastic composites were investigated, and the microscopic changes of the materials were studied by chemical component analysis. The optimal formulation of bamboo powder/PBS composite material has been identified through experimentation, yielding a flexural strength of 24.87 MPa and a compressive strength of 29.74 MPa. This material can be used for outdoor furniture, wall panels, flooring, road barriers, and other applications, providing a new environmentally friendly approach to the consumption of residual bamboo materials.
Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. Here we report that disruption of the Kruppel-like factor 14 (KLF14) gene in mice causes centrosome ...amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of Plk4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce Plk4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon tumorigenesis. Our findings reveal that KLF14 reduction serves as a mechanism leading to centrosome amplification and tumorigenesis. On the other hand, forced expression of KLF14 leads to mitotic catastrophe. Collectively, our findings identify KLF14 as a tumour suppressor and highlight its potential as biomarker and therapeutic target for cancer.
A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and ...sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
Bamboo scrimber is acknowledged for its eco-friendly potential as a structural material. Its properties are significantly affected by both its density and resin content, but the effect of resin ...content on the properties under high density is not yet known. In this study, the microstructure, water resistance, mechanical properties, and thermal stability of bamboo scrimbers with varying resin content at a density of 1.30 g/cm
were investigated. The results unearthed that phenolic resin assisted in the densification of bamboo cells during hot pressing, and a higher resin content could effectively reduce the cracks in the scrimber. The inherent cellulose I structure remained unaffected, but an increase in resin content led to a noticeable decline in crystallinity. Additionally, an increase in resin content pronouncedly improved the water resistance and dimensional stability of bamboo scrimbers. The water absorption and thickness swelling were as low as 9.67% and 7.62%, respectively. The modulus of rupture (MOR) exhibited a marginal increase with the amount of resin, whereas the compressive strength and short-beam shearing strength first increased and then decreased. Their peak strengths were 327.87 MPa at a resin content of 15 wt.%, and 168.85 MPa and 25.96 MPa at 11 wt.%, respectively. However, phenolic resin accelerated the thermal decomposition of bamboo scrimbers, and more resin worsened the thermal stability. These research outcomes offer a dual advantage, providing both a theoretical foundation and concrete data that can inform the production and practical application of high-density bamboo scrimbers.
The NAD-dependent deacetylase SirT1 regulates factors involved in stress response and cell survival and is a potential drug target of activators and inhibitors. Determination of SirT1 function in ...tumor cells is important for its targeting in cancer therapy. We found that SirT1 knockdown by short hairpin RNA accelerates tumor xenograft formation by HCT116 cells, whereas SirT1 overexpression inhibits tumor formation. Furthermore, pharmacological inhibition of SirT1 stimulates cell proliferation under conditions of growth factor deprivation. Paradoxically, SirT1 inhibition also sensitizes cells to apoptosis by chemotherapy drugs. Immunohistochemical staining revealed high level SirT1 in normal colon mucosa and benign adenomas. SirT1 overexpression was observed in ∼25% of stage I/II/III colorectal adenocarcinomas but rarely found in advanced stage IV tumors. Furthermore, ∼30% of carcinomas showed lower than normal SirT1 expression. This pattern is consistent with SirT1 having pleiotropic effects during cancer development (anti-proliferation and anti-apoptotic). These results suggest a rationale for the use of SirT1 activators and inhibitors in the prevention and treatment of colon cancer.
Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and ...cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGγ-dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGγ knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGγ-proteasome inhibition has a potential to provide tumour-starving benefits.
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