Jul 2026· Cell Chemical Biology· 0 citations· 45 references
Medicine
TL;DR
This study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.
Abstract
Proper subcellular protein localization is fundamental for protein function, yet cancer cells often exploit this machinery for survival. While the nuclear import receptor KPNB1 (importin β1) is overexpressed in various cancers, its oncogenic mechanisms remain incompletely understood and its therapeutic targeting remains in infancy. Through screening of an FDA-approved compound library, we uncovered simeprevir (Sim) and lusutrombopag (Lus) as direct KPNB1 inhibitors that disrupt its import complex assembly. These compounds blocked KPNB1-mediated nuclear import of p65, thereby suppressing Bcl-2 transcription and activating mitochondrial apoptosis. Overexpression of KPNB1, p65, or Bcl-2, but not nuclear localization signal (NLS)-deleted p65, reversed the effect of Sim/Lus. Sim induced apoptosis in multiple cancer cell lines by downregulating Bcl-2 expression and suppressed A549 xenografts growth without observable toxicity. Analysis of The Cancer Genome Atlas (TCGA) datasets substantiated the clinical relevance of the KPNB1-p65-Bcl-2 axis. Our study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.
Exportin 1 (XPO1) is a key nuclear export receptor that mediates the nuclear export of tumor suppressor proteins and growth-regulatory mRNAs from the nucleus to the cytoplasm. In several types of cancer, XPO1 is overexpressed or hyperactivated, leading to aberrant cytoplasmic sequestration of key tumor suppressors such as p53, p21, p73, FOXO and Rb. This mislocalization abrogates their nuclear transcriptional functions, disrupting cell cycle arrest, apoptosis and DNA repair, thereby promoting uncontrolled proliferation, survival and therapy resistance. Targeting XPO1 with selective inhibitors of nuclear export (SINE) has emerged as a promising anticancer strategy. The present review systematically examines the molecular mechanisms of XPO1-driven tumorigenesis and its rationale as a therapeutic target. The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT-330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies. Ongoing clinical trials and future directions to optimize therapeutic efficacy are also highlighted. Collectively, the present review aims to provide a comprehensive foundation for advancing basic and clinical research on XPO1-targeted therapies.
MYCN is a key oncogenic driver in hepatocellular carcinoma (HCC) and a therapeutic challenge due to the historical undruggability of MYC transcription factors (TFs). Using a high-throughput MYCN promoter-luciferase reporter, we identified PhiKan 083 (PK83), a small molecule previously recognized as a mutant p53 activator, that dose-dependently suppresses MYCN expression in HCC cells. PK83 impaired the proliferation and survival of MYCN-high HCC cells, inducing DNA damage, apoptosis, and loss of clonogenic and spheroid growth potential, while sparing MYCN-low HCC cells and normal hepatocytes. Structure-activity analysis revealed that polar, hydrogen-bond-capable substituents on PK83's tricyclic scaffold are critical for its activity. Although PK83 broadly activates p53 signaling, its cytotoxicity in MYCN-high cells is not strictly dependent on intact p53, as confirmed in p53-knockout systems. Transcriptome profiling and pathway analysis demonstrated robust suppression of MYC/MYCN targets along with modulation of pathways linked to stress, differentiation, and metabolism. In primary HCC tumors, PK83-downregulated TFs, including oncogenic TFs ZMIZ1 and TARBP1, positively correlated with MYCN, whereas upregulated stress-responsive TFs ATF3 and FOSL2 showed a negative correlation. These findings suggest that PK83 suppresses MYCN expression and preferentially affects MYCN-high HCC cells in a p53-independent manner, warranting further preclinical investigation of PK83 and related compounds in MYCN-associated cancers.
Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in EGFR-mutated non–small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.
Fang-Tsyr Lin, Shwu-Jiuan Lin, Kang Liu et al.· Science Advances· 0 citations
Abstract The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
BACKGROUND
Acute myeloid leukemia (AML) has a poor prognosis due to high chemoresistance and recurrence. TRIM24, an E3 ubiquitin ligase, is oncogenic in solid tumors, but its role in AML and regulation of the oncoprotein p110 CUX1 remain unclear.
METHODS
We performed bioinformatic analysis to assess TRIM24 expression, prognosis, and protein-protein interactions. Functional studies used genetic manipulation and pharmacological inhibition in AML cells. Protein interactions were examined by Co-IP, IP-MS, and immunofluorescence. The stability and ubiquitination of p110 CUX1 were examined via CHX chase assays and ubiquitination profiling. The biological and therapeutic significance of the identified axis was validated using cell proliferation, apoptosis assays, drug sensitivity tests, and a CDX mouse model.
RESULTS
TRIM24 is overexpressed in AML and predicts poor prognosis. TRIM24 promotes proliferation and inhibits apoptosis. Mechanistically, TRIM24 functions as a scaffold-like adaptor to recruit USP10 to deubiquitinate and stabilize p110 CUX1 via K48-linked ubiquitin chain cleavage. The TRIM24/USP10/p110 CUX1 axis activates the MAPK signaling pathway, with CUX1 regulating ERK transcription. TRIM24 overexpression enriches DNA repair pathways, conferring cytarabine resistance. Targeting TRIM24 genetically or with dTRIM24 sensitizes AML cells to cytarabine in vitro and in vivo.
CONCLUSION
Our study reveals a novel non-canonical role of TRIM24 as a stabilizer of the p110 CUX1 oncoprotein by recruiting USP10. This TRIM24/USP10/p110 CUX1 axis is critical for AML progression, clinical prognosis, and chemoresistance, presenting a promising therapeutic target for AML treatment.
Zhiyin Ke, Jie Li, L. Zhong et al.· Journal of Translational Med...· 0 citations
BACKGROUND
Extensive clinical evidence has identified metastasis-associated colon cancer 1 (MACC1) as a pivotal cancer-promoting gene that actively fuels the advancement of neoplasms. However, the upstream transcriptional regulators of MACC1 and the specific posttranscriptional mechanisms involving N6-methyladenosine (m6A) modification that govern its expression remain largely undefined. This study aims to elucidate the regulatory network controlling MACC1 expression and its impact on colorectal cancer (CRC) progression.
METHODS
MACC1 expression and its potential regulators were systematically analyzed using public databases, including GEPIA, TCGA, and TIMER2, alongside clinical tissue samples and cell lines (SW480, HCT-116, and SW620). Functional experiments were conducted to assess cell viability, proliferation, invasion, and ferroptosis. These methodological approaches encompassed chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), as well as dual-luciferase reporter systems. Furthermore, in vivo validation was performed using a nude mouse xenograft model.
RESULTS
MACC1 was significantly upregulated in CRC tissues and cell lines, and its high expression correlated with an unfavorable prognosis. Functional assays revealed that silencing MACC1 inhibited CRC cell proliferation and invasion while inducing ferroptosis. Mechanistically, RNA binding protein 15 (RBM15) was identified as a key m6A methyltransferase component that stabilized MACC1 mRNA in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)- dependent manner. Furthermore, zinc finger and BTB domain-containing 33 (ZBTB33) was found to transcriptionally activate RBM15 by binding to its promoter region. Knockdown of RBM15 inhibited CRC cell invasion and proliferation and induced ferroptosis; these effects were notably reversed by MACC1 overexpression. Moreover, ZBTB33 silencing inhibited the key malignant phenotypes of CRC cells and induced ferroptosis by regulating RBM15. Further, RBM15 depletion suppressed tumor growth, which was attenuated by the restoration of MACC1.
DISCUSSION
Our study unveils a novel ZBTB33/RBM15/MACC1 signaling axis that drives CRC progression. Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.
CONCLUSION
These findings uncover a novel ZBTB33/RBM15/MACC1 regulatory axis in CRC, where ZBTB33 transcriptionally activates RBM15 to enhance MACC1 mRNA stability, ultimately suppressing ferroptosis and promoting tumor progression.
Lichun Wang, Bin Guo, Xueping Jiao et al.· Current Gene Therapy· 0 citations