The nuclear pore complex protein RANBP2 has emerged as a critical factor in the development and progression of various solid malignancies. As a SUMO E3 ligase, RANBP2 works out a post-translational modification calle SUMOylation, which is essential for regulating the cell cycle. Recent insights have highlighted the multifaceted involvement of RANBP2 in tumorigenesis, suggesting its potential as a therapeutic target for cancer treatment. SUMOylation is a crucial process that influences oncogenes and other cell cycle regulators, making it highly relevant in cancer biology. Among the SUMO E3 ligases, RANBP2, located within the nuclear pore complex (NPC), has drawn particular attention due to its involvement in both nucleocytoplasmic transport and mitosis regulation.
Its interaction with other cellular components and the modulation of protein SUMOylation have linked RANBP2 to cancers like hepatocellular carcinoma (HCC), cholangiocarcinoma, gastric, breast, cervical and prostate cancer. In liver cancer RANBP2 influences the expression of epidermal growth factor receptor member HER2 through SUMOylation of LASP1, promoting cancer cell proliferation. Moreover, its interaction with the orphan receptor Liver Receptor Homologue-1 (LRH-1) modulates alpha-fetoprotein (AFP) levels, while its role in the SUMOylation of IL-33 impacts immune evasion. The SUMOylation by RANBP2 disrupts the ubiquitin-mediated protein degradation of interferon regulatory factor 1 (IRF1) and transcriptionally enhancing the expression of PD-L1, an immune-supporting factor in the tumor microenvironment.
In addition, SUMOylated nuclear IL-33 can promote the production of interleukin 8 (IL-8), which stimulates the IL-8 signaling pathway in macrophages, thereby promoting the migration and polarization of macrophages to the tumor-permissible phenotype. Overall, it is warranted to unravel the intricate mechanisms through which IL-33 exerts its effects in HCC, ultimately offering new insights for the development of therapeutic strategies targeting this cytokine in the context of liver cancer. In cholangiocarcinoma, RANBP2-mediated SUMOylation of p27kip1 promotes tumor cell proliferation by facilitating its nuclear translocation. p27kip1 serves as a crucial cell cycle regulator by inhibiting cyclin-dependent kinases, particularly during the transition from the G1 to S phase.
In gastric cancer, RANBP2 interacts with DAXX, promoting the nuclear localization of this protein, which correlates with poor prognosis. DAXX acts as a transcriptional corepressor, influencing gene expression, and is also involved in cell death and development. DAXX is a histone chaperone, constitutively associated to the death receptor Fas/APO-1 and may play a role in chromatin remodeling and DNA repair in conditions of non-apoptotic Fas engagement, as many years ago found in glioblastoma cells. Meanwhile, in breast cancer, the SUMOylation of β-arrestin 2 by RANBP2 disrupts the MDM2-p53 signaling axis, and enhances p53 activity to induce cell death. Additionally, in cervical cancer, RANBP2 enhances TCF4 activation through SUMOylation, facilitating the Wnt/β-catenin signaling pathway that drives tumor progression.
In prostate cancer, RANBP2’s regulation of p53 SUMOylation modulates androgen receptor-mediated pathways, affecting cancer proliferation. Emerging research also associates RANBP2 with other solid tumors, including glioblastoma, oral cancer, colorectal cancer, and lung cancer. In glioblastoma, RANBP2’s role in SUMOylation appears linked to DNA repair and chromatin organization, while in colorectal cancer, its depletion disrupts mitotic spindle stability, promoting apoptosis. In lung cancer, RANBP2’s interaction with DNA Topoisomerase II hints at its involvement in maintaining genetic integrity during cell division. Lung cancer remains a pervasive global challenge, resulting in a greater number of fatalities among men than any other cancer worldwide. Exploiting RANBP2 pharmacological modulation in this cancer could open specific curative opportunities.
Nonetheless, given its extensive involvement in multiple cancers, targeting RANBP2 could open new avenues for therapeutic intervention. For example, a very recent investigation revealed that the antibiotic drug Clofoctol effectively reduced the β-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of gastric cancer cells. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding right to RANBP2, thereby suppressing the SerpinE1/β-catenin axis. Clofoctol is a rarely used synthtic antibiotic, active aginst Gram-positive cocci and possesses a good safety profile. It would be interesting to assess how its effecctve anticancer doses and toxicity profile would match for the best employment in cancer therapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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