Guan Han, Hu Qiang, Wan Lilin, Wang Can, Xue Yifeng, Feng Ninghan, Zhao Chenggui, Chen Ming, You Zonghao
Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China.
Cancer Med. 2025 May;14(9):e70887. doi: 10.1002/cam4.70887.
Chemotherapy and androgen-deprivation treatment are the curative approaches utilized to suppress prostate cancer (PCa) progression. However, drug resistance and metastasis are extensive and hard to overcome even though remarkable progress has been made in recent decades. The cancer stem cell-related theoretical model explains the distinct molecular characteristics of cancer, its relapse, metastasis, and drug resistance. Meanwhile, noncoding RNA functions in the formation of drug resistance and metastasis in most cancers. The long intergenic nonprotein coding RNA 908 (LINC00908) has been reported to restrain cell proliferation, migration, and invasion of some cancers like triple-negative breast cancer, diffuse large B-cell lymphoma, PCa, and so on. However, its role in stemness for PCa remains unclear.
We delved into the impact of LINC00908 in PCa cell stemness and the principal molecular mechanism. Then, the impact of LINC00908 on PCa cell stemness and its corresponding mechanism was explored by using functional assays and bioinformatics evaluation.
We found that LINC00908 was low-expressed in PCa cells, and it exerted suppressive functions in PCa cell stemness and tumor growth. Additionally, we revealed that LINC00908 down-regulation was mediated by the HDAC2-p300-YY1 transcription complex. Moreover, LINC00908 up-regulated glycogen synthase kinase 3 beta (GSK3B) via sponging miR-3179. Meanwhile, LINC00908 deployed DEAD-box helicase 3 X-linked (DDX3X) to facilitate the stabilization of F-box and WD repeat domain containing 2 (FBXW2) mRNA. Importantly, LINC00908 enhanced GSK3B and FBXW2 expression to induce the ubiquitination of β-catenin protein, leading to Wnt pathway inactivation.
These results reveal that LINC00908 inhibits PCa cell stemness via inactivating the GSK3B/FBXW2-regulated Wnt pathway, which might enrich people's knowledge of PCa stemness and provide some new potential biomarkers for PCa.
化疗和雄激素剥夺治疗是用于抑制前列腺癌（PCa）进展的治疗方法。然而，尽管近几十年来取得了显著进展，但耐药性和转移现象广泛存在且难以克服。癌症干细胞相关的理论模型解释了癌症独特的分子特征、复发、转移和耐药性。同时，非编码RNA在大多数癌症的耐药性和转移形成中发挥作用。据报道，长链基因间非编码RNA 908（LINC00908）可抑制三阴性乳腺癌、弥漫性大B细胞淋巴瘤、PCa等某些癌症的细胞增殖、迁移和侵袭。然而，其在PCa干性中的作用仍不清楚。
我们深入研究了LINC00908对PCa细胞干性的影响及其主要分子机制。然后，通过功能测定和生物信息学评估，探讨了LINC00908对PCa细胞干性的影响及其相应机制。
我们发现LINC00908在PCa细胞中低表达，并且它在PCa细胞干性和肿瘤生长中发挥抑制作用。此外，我们发现LINC00908的下调是由HDAC2-p300-YY1转录复合物介导的。此外，LINC00908通过海绵吸附miR-3179上调糖原合酶激酶3β（GSK3B）。同时，LINC00908利用X连锁的DEAD盒解旋酶3（DDX3X）促进含F盒和WD重复结构域2（FBXW2）的mRNA的稳定性。重要的是，LINC00908增强GSK3B和FBXW2的表达，诱导β-连环蛋白的泛素化，导致Wnt通路失活。
这些结果表明，LINC00908通过使GSK3B/FBXW2调节的Wnt通路失活来抑制PCa细胞干性，这可能丰富人们对PCa干性的认识，并为PCa提供一些新的潜在生物标志物。
