Ciaramella Vincenza, Belli Valentina, Izzo Francesco, Belli Andrea, Avallone Antonio, De Stefano Alfonso, Soricelli Andrea, Grimaldi Anna Maria
IRCCS SYNLAB SDN, 80143 Naples, Italy.
Unit of Hepato-Biliary and Pancreatic Surgery, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Naples, Italy.
Int J Mol Sci. 2025 Jul 30;26(15):7385. doi: 10.3390/ijms26157385.
The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression.
染色质盒（CBX）家族包含通过染色质修饰参与转录抑制的关键表观遗传调节因子。多梳CBX蛋白的失调与表观遗传基因沉默和癌症进展有关。然而，CBX家族成员在结直肠癌（CC）中的具体作用和预后价值仍不清楚。在本研究中，我们发现与正常结直肠组织相比，CBX基因在CC组织和细胞模型中显著失调。其中，CBX4和CBX8是肿瘤中上调最明显的异构体。功能分析表明，CBX4过表达增强CC细胞增殖，而其沉默则降低肿瘤生长。同样，在患者来源的肿瘤类器官中对CBX4进行药理抑制导致增殖减少，支持其促肿瘤作用。免疫荧光分析进一步揭示了CBX4抑制后NF-κB信号通路的改变，以及包括NF-κB、TNF、IL-1和c-Myc在内的通路成分mRNA水平的降低。这些发现表明CBX4与CC中炎症相关通路之间存在潜在的相互作用。总体而言，我们的研究突出了CBX4在结直肠癌中的致癌作用，并支持其作为疾病进展的新型治疗靶点和早期生物标志物的潜力。
