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X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.

Metabolic reprogramming is a hallmark of cancers crucial for fulfilling the needs of energy, building blocks, and antioxidants to support tumor cells' rapid proliferation and to cope with the harsh microenvironment. Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family whose expression is up-regulated in various tumors, however, whether it is involved in tumor cell metabolic reprogramming remains unclear. Herein, we report that PBX3 is a positive regulator of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). PBX3 promoted G6PD transcriptional activity in tumor cells by binding directly to its promoter, leading to PPP stimulation and enhancing the production of nucleotides and NADPH, a crucial reductant, thereby promoting nucleic acid and lipid biosynthesis while decreasing intracellular reactive oxygen species levels. The PBX3/G6PD axis also promoted tumorigenic potential in vitro and in vivo. Collectively, these findings reveal a novel function of PBX3 as a regulator of G6PD, linking its oncogenic activity with tumor cell metabolic reprogramming, especially PPP. Furthermore, our results suggested that PBX3 is a potential target for metabolic-based anti-tumor therapeutic strategies.

Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties. Cells in tumor tissue sense mechanical signals from the tumor microenvironment, which consequently drive the acquisition of hallmarks of cancer, including sustained proliferative signaling, evading growth suppressors, apoptosis resistance, sustained angiogenesis, metastasis, and immune evasion. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanically sensitive ion channel protein that can be activated mechanically and is closely related to various diseases. Recent studies showed that Piezo1 mediates tumor development through multiple mechanisms, and its overexpression is associated with poor prognosis. Therefore, the discovery of Piezo1, which links-up physical factors with biological properties, provides a new insight for elucidating the mechanism of tumor progression under a mechanical microenvironment, and suggests its potential application as a tumor marker and therapeutic target. In this review, we summarize current knowledge regarding the role of Piezo1 in regulating cancer hallmarks and the underlying molecular mechanisms. Furthermore, we discuss the potential of Piezo1 as an antitumor therapeutic target and the limitations that need to be overcome.

Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown. Herein, we found that XBP1-u promotes tumor growth by enhancing cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells. Specifically, XBP1-u colocalizes with sterol regulatory element-binding protein 2 (SREBP2) and inhibits its ubiquitination/proteasomal degradation. The ensuing stabilization of SREBP2 activates the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ), a rate-limiting enzyme in cholesterol biosynthesis. We subsequently show that the XBP1-u/SREBP2/HMGCR axis is crucial for enhancing cholesterol biosynthesis and lipid accumulation as well as tumorigenesis in HCC cells. Taken together, these findings reveal a novel function of XBP1-u in promoting tumorigenesis through increased cholesterol biosynthesis in hepatocarcinoma cells. Hence, XBP1-u might be a potential target for anti-tumor therapeutic strategies that focus on cholesterol metabolism in HCC.

Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are highly homologous, especially in their zinc‐finger domains. Furthermore, they share a consensus DNA binding motif. Increasing evidences have demonstrated the tumor suppressive effect of YY2, in contrast with the oncogenic YY1; however, little is known about the biological and pathological functions of YY2. Here, it is determined that YY2 induces tumor cell ferroptosis and subsequently suppresses tumorigenesis by inhibiting solute carrier family 7 member 11 (SLC7A11) transcription, leading to the decreased glutathione biosynthesis. Furthermore, YY2 and YY1 bind competitively to the same DNA binding site in the SLC7A11 promoter and antagonistically regulate tumor cell ferroptosis, thus suggesting the molecular mechanism underlying their opposite regulation on tumorigenesis. Moreover, mutations of YY2 zinc‐finger domains in clinical cancer patients abrogate YY2/SLC7A11 axis and tumor cell ferroptosis. Together, these results provide a new insight regarding the regulatory mechanism of ferroptosis, and a mechanistic explanation regarding the tumor suppressive effect of YY2. Finally, these findings demonstrate that homeostasis between YY1 and YY2 is crucial for maintaining redox homeostasis in tumor cells. Yin Yang 2 (YY2) is highly homologous with Yin Yang 1 (YY1), a famous oncogene; however, little is known about its functions. YY2 competes with YY1 to bind to SLC7A11 promoter and regulates it antagonistically, resulting in the opposite regulation on glutathione synthesis, ferroptosis, and tumor progression, indicating that YY2/YY1 homeostasis is crucial for maintaining redox homeostasis in tumors.

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. This work revealed that yin yang 2 (YY2) triggers impaired mitochondrial fission, and subsequently promotes liver CSCs pool exhaustion, by downregulating the transcriptional activity of dynamin‐related protein 1 (DRP1). These results provide new insights regarding the regulatory mechanism of mitochondria fission‐mediated CSCs asymmetric division and highlight the potential of targeting YY2/DRP1 axis as an antitumor therapeutic strategy targeting CSCs.

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. CIN is a hallmark of cancer and can drive tumorigenesis; paradoxically, high CIN correlates with better prognosis in clinical patients. The underlying cause of this paradox is still unclear. This study identifies the novel role of YY2 in modulating BUB3‐mediated SAC activity and CIN, as well as YY2/BUB3‐mediated SAC activity and CIN levels role in determining tumor cell fates.

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity, which is fundamental for 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 drug sensitivity and prognosis. However, the mechanism by which CIN determines tumor cell fates and drug sensitivity remain poorly understood. In this study, using a cross-omics approach, we identified YY2 as a mitotic regulator that peaks at M phase and promotes SAC activity by positively regulating the transcriptional activity of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While inducing CIN, YY2/SAC activity defect enhanced mitosis and tumor growth, whereas YY2/SAC hyperactivation, as a result of YY2 overexpression, triggered mitotic delay and growth suppression. Furthermore, we revealed that excessive CIN, caused by either YY2 overexpression or further inhibiting SAC activity in YY2-knocked out cells, leads to higher cell death rates. However, residual tumor cells that survived DNA damage-based therapy had moderate CIN and increased drug resistance; meanwhile YY2 overexpression in these cells sensitizes them to DNA-damage agents. Hence, this study provides insights into the regulatory mechanism of SAC activity as well as the role of YY2/BUB3 axis, SAC activity, and CIN levels in determining tumor cell fate. Furthermore, this study also links up tumor cells drug resistance with moderate CIN, and suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Updated the manuscript title to: YY2/BUB3 axis-mediated SAC hyperactivity determines tumor cell fate through chromosomal instability