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LINC00908 Inactivates Wnt/β-Catenin Signaling Pathway to Inhibit Prostate Cancer Cell Stemness via Upregulating GSK3B
Han Guan1,2, Qiang Hu2, Lilin Wan2
1Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Long intergenic nonprotein coding RNA 908 (LINC00908) suppresses prostate cancer (PCa) stemness and tumor growth by inactivating the Wnt pathway. This discovery offers potential new biomarkers for PCa treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) treatments like chemotherapy and androgen-deprivation therapy face challenges with drug resistance and metastasis.
- Cancer stem cells (CSCs) are implicated in PCa relapse, metastasis, and drug resistance.
- Noncoding RNAs, including long intergenic nonprotein coding RNA 908 (LINC00908), play roles in cancer progression, but LINC00908's function in PCa stemness is unclear.
Purpose of the Study:
- To investigate the role of LINC00908 in prostate cancer (PCa) cell stemness.
- To elucidate the molecular mechanisms underlying LINC00908's function in PCa stemness.
Main Methods:
- Functional assays were employed to assess the impact of LINC00908 on PCa cell stemness.
- Bioinformatics evaluation was utilized to explore the underlying molecular mechanisms.
- Investigated the regulatory complex HDAC2-p300-YY1 and its effect on LINC00908 expression.
- Analyzed the interaction of LINC00908 with miR-3179 and its effect on GSK3B.
- Examined the role of LINC00908 in stabilizing FBXW2 mRNA via DDX3X.
Main Results:
- LINC00908 expression was found to be low in PCa cells, exhibiting suppressive effects on PCa stemness and tumor growth.
- LINC00908 down-regulation was mediated by the HDAC2-p300-YY1 transcription complex.
- LINC00908 up-regulated glycogen synthase kinase 3 beta (GSK3B) by sponging miR-3179.
- LINC00908 stabilized F-box and WD repeat domain containing 2 (FBXW2) mRNA through DEAD-box helicase 3 X-linked (DDX3X).
- LINC00908 enhanced GSK3B and FBXW2 expression, leading to β-catenin ubiquitination and Wnt pathway inactivation.
Conclusions:
- LINC00908 inhibits PCa cell stemness by inactivating the GSK3B/FBXW2-regulated Wnt pathway.
- These findings enhance understanding of PCa stemness mechanisms.
- LINC00908 presents potential as a novel biomarker for prostate cancer.
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