YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood. Here, using a cross-omics approach, YY2 is identified as a mitotic regulator that promotes SAC activity by activating the transcription of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While both conditions induce CIN, a defect in YY2/SAC activity enhances mitosis and tumor growth. Meanwhile, hyperactivation of SAC mediated by YY2/BUB3 triggers a delay in mitosis and suppresses growth. Furthermore, it is revealed that YY2/BUB3-mediated excessive CIN causes higher cell death rates and drug sensitivity, whereas residual tumor cells that survived DNA damage-based therapy have moderate CIN and increased drug resistance. These results provide insights into the role of SAC activity and CIN levels in influencing tumor cell survival and drug response, as well as suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.

The two sides of chromosomal instability: drivers and brakes in cancer.

Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule-kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the "just-right" model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

NeuroD1-GPX4 signaling leads to ferroptosis resistance in hepatocellular carcinoma.

Cell death resistance is a hallmark of tumor cells that drives tumorigenesis and drug resistance. Targeting cell death resistance-related genes to sensitize tumor cells and decrease their cell death threshold has attracted attention as a potential antitumor therapeutic strategy. However, the underlying mechanism is not fully understood. Recent studies have reported that NeuroD1, first discovered as a neurodifferentiation factor, is upregulated in various tumor cells and plays a crucial role in tumorigenesis. However, its involvement in tumor cell death resistance remains unknown. Here, we found that NeuroD1 was highly expressed in hepatocellular carcinoma (HCC) cells and was associated with tumor cell death resistance. We revealed that NeuroD1 enhanced HCC cell resistance to ferroptosis, a type of cell death caused by aberrant redox homeostasis that induces lipid peroxide accumulation, leading to increased HCC cell viability. NeuroD1 binds to the promoter of glutathione peroxidase 4 (GPX4), a key reductant that suppresses ferroptosis by reducing lipid peroxide, and activates its transcriptional activity, resulting in decreased lipid peroxide and ferroptosis. Subsequently, we showed that NeuroD1/GPX4-mediated ferroptosis resistance was crucial for HCC cell tumorigenic potential. These findings not only identify NeuroD1 as a regulator of tumor cell ferroptosis resistance but also reveal a novel molecular mechanism underlying the oncogenic function of NeuroD1. Furthermore, our findings suggest the potential of targeting NeuroD1 in antitumor therapy.

The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers.

Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions.

Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.

YY2-DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division.

Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross-omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem-like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor-initiating capacity. Meanwhile, YY2 knock-out in stem-like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin-related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic-mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.

The biological implications of Yin Yang 1 in the hallmarks of cancer.

Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress-related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc-finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1-related non-coding RNAs in acquiring cancer-specific characteristics. Therefore, these YY1-related non-coding RNAs are also crucial for YY1-mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.

Glucosamine decreases the stemness of human ALDH+ breast cancer stem cells by inactivating STAT3.

Cancer stem cells (CSCs) are a subpopulation of cancer cells responsible for tumor maintenance and relapse due to their ability to resist various anticancer effects. Owing to the resistance of CSCs to the effects of targeted therapy, an alternative strategy that targets post-translational glycosylation may be an improved approach to treat cancer as it disrupts multiple coordinated signaling that maintains the stemness of CSCs. Glucosamine acts as an anticancer agent possibly by inhibiting N-linked glycosylation. The aim of the present study was to investigate the effect of glucosamine on the stemness of breast CSCs, which is regulated by signal transducer and activator of transcription 3 (STAT3) signaling. Human aldehyde dehydrogenase-positive (ALDH+) breast CSCs and MCF7 cells were treated with various concentrations (0.25, 1 or 4 mM) of glucosamine for 24 h. Subsequently, cell viability was determined by performing a trypan blue exclusion assay, pluripotency gene [ALDH 1 family member A1 (ALDH1A1), octamer-binding transcription factor 4 (OCT-4), and Krüppel-like factor 4 (KLF4)] expression was determined using the reverse transcription-quantitative polymerase chain reaction, and STAT3 and phosphorylated STAT3 (pSTAT3) levels were determined by performing western blot analysis. Furthermore, the number of mammosphere-forming units (MFUs) in ALDH+ breast CSCs and MCF7 cells was determined. It was determined that glucosamine treatment decreased the viability of ALDH+ breast CSCs. Glucosamine treatment also decreased the stemness of ALDH+ breast CSCs and MCF7 cells, as indicated by decreased ALDH1A1, OCT-4 and KLF4 expression level, and a decreased number of MFUs. This effect of glucosamine may be associated with a decreased pSTAT3/STAT3 ratio, indicating that glucosamine inhibited STAT3 activation; therefore, the results of the present study indicated that glucosamine treatment may be an improved approach to target the stemness of CSCs.

Metabolic Interplay between Tumour Cells and Cancer-Associated Fibroblasts (CAFs) under Hypoxia versus Normoxia.

The growth of tumour cells is closely related to cancer-associated fibroblasts (CAFs) present within their microenvironment. CAFs, the most abundant cells in tumour stroma, secrete growth factors that play pivotal roles in tumour cell proliferation, metabolism, angiogenesis and metastasis. Tumour cells adapt to rapid environmental changes from normoxia to hypoxia through metabolic interplay with CAFs. In this mini review, we discuss the role of lactate dehydrogenases (LDHs) and monocarboxylate transporters (MCTs) on the metabolic interplay between tumour cells and CAFs under hypoxia compared to normoxia. The LDHs catalyse the interchange of lactate and pyruvate, whereas MCTs facilitate the influx and efflux of monocarboxylates, especially lactate and pyruvate. To sum up, tumour cells switch their metabolic state between glycolysis and oxidative phosphorylation through metabolic interplay with CAFs, which exhibit the Warburg effect under hypoxia and reverse Warburg effect under normoxia.