Pharmacologic Inhibition of SOX9-CDK4 by CYD-4-61 Impairs Gastric Adenocarcinoma Growth and Amplifies Anti-PD-1 Response.

Comprehensive Analyses of SOX7 Provide Novel Insights on Its Tumor Suppressor Role and Its Target Genes with Therapeutic Implications in Multiple Myeloma

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction.

GATA3-driven CDC20 activation facilitates tumor growth and metastasis through suppressing Bax/Bcl-2 ratio and boosting EMT process in neuroblastoma.

Neuroblastoma (NB) is a heterogeneous pediatric malignancy in which many high-risk tumors lack MYCN amplification, necessitating the identification of alternative molecular drivers. Here, integrative transcriptomic analyses of MYCN-nonamplified NB cohorts identified cell division cycle 20 (CDC20) as a candidate associated with high-risk disease and metastasis. CDC20 expression was elevated in aggressive NB across subtypes and correlated with adverse clinical outcomes, with particularly informative prognostic value in MYCN-nonamplified patients. Functional studies established CDC20 as a potent oncogene promoting proliferation, migration, apoptosis resistance, and tumor progression in NB models irrespective of MYCN status. Pharmacological inhibition of CDC20further supported CDC20 as a potential therapeutic vulnerability in NB. Mechanistically, we found that the transcription factor GATA3 directly bound a specific motif within the CDC20 promoter, as validated by ChIP-qPCR and site-directed point mutagenesis, and transcriptionally activates its expression. Reciprocal genetic epistasis experiments further demonstrated that CDC20 depletion attenuated GATA3-driven oncogenic phenotypes, whereas restoration of CDC20 rescued the impaired growth, migration, and survival caused by GATA3 depletion. At the downstream level, CDC20 facilitates NB progression via dual mechanisms: suppressing the pro-apoptotic Bax/Bcl-2 ratio and inducing an epithelial-mesenchymal transition-like phenotype conducive to metastasis. Collectively, our study delineates a previously uncharacterized GATA3-CDC20 regulatory axis that promotes NB progression and identify CDC20 as a potential therapeutic vulnerability across NB subtypes, while highlighting its particular potential for risk stratification in MYCN-nonamplified disease.

The lncRNA SOX2OT Drives Non-Small Cell Lung Cancer Progression and Metastasis by Suppressing miR-143

In terms of cancer-related death, non-small cell lung cancer (NSCLC), the world’s leading cause, highlights the need for continued research into the genetic factors that influence tumor growth. Long non-coding RNAs (lncRNAs) are now well recognized as essential regulators of oncogenic signaling cascades; nevertheless, the specific role and molecular basis of the SOX2 overlapping transcript (SOX2OT) in NSCLC are not entirely understood. This study examined the functional importance of SOX2OT and its regulatory interactions with tumor-suppressive microRNAs in NSCLC cells. In A549 and Calu-3 cells, RNA interference-mediated SOX2OT silencing dramatically reduced cellular proliferation, migration, and invasiveness. Moreover, SOX2OT knockdown was associated with inhibition of epithelial–mesenchymal transition (EMT), alongside induction of cell cycle arrest and activation of apoptotic pathways. Integrated transcriptomic profiling and bioinformatic prediction analyses identified miR-143 as a putative downstream effector of SOX2OT activity. Consistently, depletion of SOX2OT resulted in marked elevation of miR-143 expression, which corresponded with downregulation of oncogenic mediators, including STAT3, EZH2, and CXCL13. As a result of SOX2OT suppression, both the transcript and the protein levels of PTEN were restored. Further functional characterization demonstrated that SOX2OT knockdown inhibits EMT progression by decreasing mesenchymal markers and EMT-related transcription factors (TFs) while concomitantly enhancing epithelial marker expression. Collectively, these findings suggest that SOX2OT contributes to NSCLC pathogenesis through regulation of a miR-143-centered signaling network that influences oncogenic signaling, cellular survival, and metastatic potential. Targeting the SOX2OT/miR-143 regulatory axis may therefore represent a promising therapeutic approach for NSCLC, while also underscoring the broader importance of lncRNA-mediated post-transcriptional regulation in lung cancer biology.

Effect of EZH2 regulation of the JAK2/STAT3 signaling pathway on proliferation and apoptosis in non‑small cell lung cancer cells.

Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in non‑small cell lung cancer (NSCLC) and is associated with aggressive tumor behavior and poor patient prognosis. However, the molecular mechanisms through which EZH2 drives NSCLC progression, particularly its interplay with major oncogenic signaling cascades, remain incompletely defined. EZH2 expression was analyzed using publicly available databases. Functional perturbations were achieved via short hairpin RNA (shRNA)‑mediated knockdown in NCI‑H1299 and A549 NSCLC cell lines. Cell proliferation, migration, invasion, apoptosis, and colony formation were assessed using Cell Counting Kit‑8, Transwell, flow cytometry and colony formation assays, respectively. Involvement of the JAK2/STAT3 pathway was examined by western blotting and rescue experiments using a JAK2 agonist. In vivo validation was conducted using a xenograft mouse model. EZH2 was markedly upregulated in NSCLC tissues. Its silencing markedly suppressed cell proliferation, impaired migratory and invasive capacities, induced apoptosis, and curtailed tumor growth in vivo. Mechanistically, EZH2 silencing attenuated the phosphorylation of both JAK2 and STAT3. Crucially, the anti‑tumor effects of EZH2 knockdown were effectively reversed by JAK2 agonism, positioning EZH2 upstream of the JAK2/STAT3 axis. The present study demonstrated that EZH2 promotes NSCLC progression through activation of the JAK2/STAT3 signaling pathway, identifying the EZH2‑JAK2/STAT3 axis as a potential therapeutic vulnerability in this malignancy.

E-cadherin-driven interleukin-6 expression promotes autophagy-mediated platinum resistance in ovarian clear cell carcinoma.

Pharmacological inhibition of CDK7 and CDK9 suppresses gastrointestinal (colon) cancer progression through modulation of stemness, epithelial-mesenchymal transition, and chemoresistance.