Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the poorly responsive to current therapeutics. There is an emergent need to develop new therapies as well as new predictive and prognostic biomarkers. Several mechanisms have been reported in PDAC that underlie the tumor aggressiveness and its highly intrinsic resistance. One factor that has been revealed is the overexpression of the epigenetic enhancer of zeste homolog 2 (EZH2) in PDAC and that plays a central role in its pathogenesis, malignancy, and resistance to conventional therapies and immune evasion. EZH2 is a catalytic component of the polycomb repressive complex 2 (PRC2) that regulates and represses gene expression. EZH2-mediated epigenetic silencing via the trimethylation of lysine 27 of histone H3 (H3K27me3) is also involved in the suppression of tumor suppressors and anti-apoptotic genes and the activation of genes involved in cell cycle progression, cell proliferation, and differentiation. High EZH2 expression in PDAC correlates with lymph node metastases, advanced clinical stage, and is an indicator of poor prognosis. While current treatment with checkpoint inhibitors resulted in significant clinical responses in various cancers, however, it failed in PDAC due to EZH2-induced immune evasion and contribution to a highly immunosuppressive tumor microenvironment (TME). Various EZH2 inhibitors have been developed, but not clinically effective in PDAC. Alternative approaches targeting EZH2 are proposed.
Overexpression of the transcription factor Yin Yang 1 (YY1) is frequently observed in non-Hodgkin lymphoma (NHL) and is associated with the upregulation of the anti-apoptotic protein Bcl-2 and the oncogene c-Myc, facilitating tumor progression. Current literature demonstrates these factors co-interact to facilitate aberrant signaling pathways promoting resistance mechanisms. This paper will briefly outline the role of the YY1-Bcl2-cMyc axis in NHL and further establish this axis through bioinformatics analysis of public data sets. Specifically, bioinformatic analyses revealed all three factors fostered a significant positive relationship with one another in DLBCL, as well as the coordinated upregulation of YY1, c-Myc, and Bcl-2 in tumor tissues. Furthermore, immune infiltration analyses on public data sets revealed that the expression of YY1, c-Myc, and Bcl-2 significantly associated with the presence and activity of various immune cells (i.e., B cells, CD8 + T cells, NK Cells, M2 macrophages) and non-immune cells (CLPs and HSCs) in the TME. We observed increased infiltration of M2 macrophages in both YY1 and Bcl-2-which can be a potential shared mechanism to promote an immunosuppressive environment. Data on mutation frequency and survival prognosis (i.e., Kaplan-Meier analysis) was also compiled between different NHL patient cohorts to provide context onto the implications of a dysregulated YY1-Bcl-2-c-Myc axis in NHL.
Colorectal cancer (CRC) remains a significant health challenge worldwide, and tumor recurrence, metastasis, and therapeutic resistance are mainly facilitated by cancer stem cells (CSC). Aberrant activation of the β-catenin driven Wnt signaling pathway, that fosters tumor initiation, self-renewal, and stemness-related gene expression, is central to the preservation of CSC properties. This review elucidates how β-catenin regulated transcriptional networks support CSC phenotypic nature such as self-renewal, differentiation potential, and survival advantages that make CRC aggressive. We discuss important β-catenin target genes and their roles in controlling stemness, proliferation, evasion of the immune system, chemoresistance and metabolic adaptation. We explore the challenges and knowledge gaps in therapeutic targeting of CRC including; tumor heterogeneity, tumor plasticity and absence of robust, predictive biomarkers. In our conclusion we discuss future directions toward better targeting of β-catenin-driven CSC programs that place importance on integrated, multi-modal approaches to target both the cellular and molecular heterogeneity of CRC with the goal of improving outcome and improving relapse rates.
Pre-B-cell leukemia homeobox 3 (PBX3) is a homeobox transcription factor that belongs to the pre-B-cell leukemia homeobox family. Studies have revealed that PBX3 plays crucial roles in tumor progression and metastasis. PBX3 upregulation has been linked to various tumors, where it contributes to cell growth and development. One of its primary functions in tumor biology is promoting cell proliferation by modulating the cell cycle. Moreover, PBX3 inhibits apoptotic pathways, allowing tumor cells to survive and resist treatment. In addition to its role in survival, PBX3 is involved in epithelial-mesenchymal transition (EMT) and enhances the invasive potential, contributing to tumor spread. It also exerts its effects through interactions with other transcription factors, including homeobox proteins, and by forming complexes that bind to specific DNA sequences, activating or repressing target gene expression. Given its central role in tumor progression, PBX3 presents a promising diagnostic and therapeutic target. The development of PBX3-specific therapies, such as proteolysis-targeting chimeras (PROTACs), could provide a novel approach for tumor treatment. While challenges remain in achieving selectivity and minimizing off-target effects, PBX3-targeted therapies have the potential to improve patient outcomes, particularly for tumors characterized by PBX3 overexpression.
Dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, plays a pivotal role in cancer progression by modulating diverse oncogenic processes. This review highlights the multifaceted contributions of DRP1 to tumorigenesis, emphasizing its involvement in metabolic reprogramming, metastasis, drug resistance, cancer stem cell (CSC) maintenance, and cell death regulation. DRP1 drives metabolic shifts, such as enhanced glycolysis and fatty acid oxidation, to fuel tumor growth and survival. It promotes metastasis by facilitating epithelial-mesenchymal transition (EMT), mitochondrial dynamics, and oxidative stress regulation. DRP1 also mediates chemoresistance through mitochondrial fission-dependent mechanisms and modulates CSC stemness via asymmetric division and metabolic plasticity. Furthermore, DRP1 influences apoptosis and ferroptosis, making it a potential therapeutic target. Pharmacological inhibition of DRP1 has shown promise in sensitizing tumors to therapy and suppressing CSC populations. This review underscores DRP1 as a critical nexus in cancer biology, with broad implications for developing targeted anticancer strategies.
Ying Yang 2 (YY2), a member of the Yin Yang (YY) transcription factor family characterized by C2H2-type zinc finger domains, has emerged as a pivotal yet paradoxical regulator in tumor biology. While structurally homologous to YY1, YY2 exhibits context-dependent dual roles in different cancers: in hepatocellular carcinoma (HCC), it functions as a tumor suppressor by directly inhibit cholesterol synthesis; whereas in esophageal carcinoma, YY2 acts as an oncogenic facilitator by upregulating the expression of key glycolytic genes PDHA1/PDK3, thereby promoting metabolic reprogramming of tumor cells. This review systematically synthesizes current understanding of YY2 multifaceted roles in metabolic reprogramming regulation, cancer stem cell maintenance, ensuring chromosomal stability, and remodeling tumor immune microenvironment. We particularly highlight YY2 functional duality-its ability to suppress tumor initiation while paradoxically promoting therapy resistance in advanced cancers. Collectively, these findings position YY2 as a key multifaceted transcriptional regulator linking metabolic pathways, genomic stability, and immune responses in cancer cells.
Intratumoral immunotherapy represents a promising frontier in the treatment of sarcomas, aiming to transform immunologically "cold" tumors into "hot" ones capable of generating systemic antitumor responses. Building on William Coley's early work with bacterial infections, modern intratumoral therapies induce the cancer immunity cycle by delivering immune-activating agents directly into tumors to stimulate local and systemic immunity while minimizing systemic toxicity. This review summarizes key strategies under investigation for sarcomas, including cancer vaccines (e.g., LTX-315), cytokines and immunomodulators (e.g., STING agonists), pattern recognition receptor agonists (e.g., TLR4/9 agonists), oncolytic virotherapy (e.g., T-VEC, JX-594), cytotoxic agents (e.g., INT230-6), and cell-based therapies (e.g., dendritic cell injections). These agents are also being evaluated in combination with systemic immunotherapies and local therapies such as radiation. Early clinical trials and preclinical studies demonstrate feasibility, safety, and signs of immune activation, though consistent clinical efficacy remains to be established. Since sarcomas typically exhibit poor immunogenicity due to low tumor mutational burden and immunosuppressive tumor microenvironments, future research is needed to optimize delivery strategies, identify predictive biomarkers, and integrate intratumoral approaches with other emerging immunotherapies to induce the cancer immunity cycle. Collectively, intratumoral immunotherapy may play a transformative role in overcoming resistance and enhancing outcomes for patients with sarcoma.
The c-Jun N-terminal protein kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family. JNK1, JNK2, and JNK3 are three isoforms encoded by distinct genes. JNK signaling controls a variety of biological functions, such as cell proliferation, survival, apoptosis, and differentiation. Additionally, it controls the death and survival of cancer cells. Many studies show that JNK-driven tumorigenesis plays a major role in various cancers. Because JNKs are potential targets for cancer therapy since they are activated aberrantly in many cancers, the development of efficient and specific JNK inhibitors is the current focus in cancer therapeutics. This review provides insights into the development of new JNK inhibitors for the treatment of cancer and enhances understanding of JNK's involvement in cancer progression.
Colon cancer (CC) is the 3rd most prevalent cancer globally, following breast and lung cancer, with the second-highest mortality rate. Multiple risk factors contribute to CC, and metastasis is the primary cause of increased mortality among CC patients. Natural compounds have been investigated for their ability to concurrently influence various carcinogenic mechanisms by interfering with the expression or activity of their signaling targets. This review focuses on natural flavonoids such as quercetin, taxifolin, and rutin. We discuss how these bioactive compounds potentially mitigate metastasis and associated signaling pathways in colon cancer.
