ORIGINAL PAPER
RAB40C regulates SNX9 stability via the ubiquitin-proteasome system and modulates the Hippo signaling pathway of prostate adenocarcinoma
1
Department of Urology, Minhang Hospital, Fudan University, Shanghai 201199, China
These authors had equal contribution to this work
Submission date: 2024-01-12
Final revision date: 2024-09-26
Acceptance date: 2024-10-03
Online publication date: 2026-01-23
KEYWORDS
ABSTRACT
Introduction:
Aim of the study was to investigate the roles and interaction mechanisms of RAB40C and SNX9 in prostate adenocarcinoma (PRAD) progression and their impact on the Hippo signaling pathway. PRAD is a significant health concern, and understanding the molecular underpinnings is essential for its effective management. Objective of this study was to identify key genes and pathways involved in PRAD using weighted gene co-expression network analysis (WGCNA) and determine the functional implications of RAB40C and its relationship with SNX9.
Material and Methods:
WGCNA was used to chart gene co-expression patterns in PRAD. Functional enrichment analyses of significant modules were performed, and prognostic insights were derived through differential gene expression analysis. The interaction between RAB40C and SNX9 was elucidated using various in vitro assays and databases.
Results:
WGCNA identified a module (MEblue) highly correlated with PRAD. The hub gene was revealed, with RAB40C being central to PRAD progression. The knockdown of RAB40C inhibited PRAD cell proliferation, migration, and invasion. SNX9 was identified as a substrate protein interacting with RAB40C. The silencing of RAB40C led to increased SNX9 expression, suggesting an inverse regulatory relationship. RAB40C promoted SNX9 degradation via the ubiquitin-proteasome pathway. Silencing RAB40C reduced PRAD cell proliferation, migration, and invasion, effects that were counteracted by simultaneous SNX9 suppression. The interaction between RAB40C and SNX9 influenced target proteins of the Hippo signaling pathway.
Conclusions:
RAB40C is essential for the progression of PRAD, partly through modulating SNX9 levels and the Hippo signaling pathway. This interplay offers novel insights for PRAD therapeutic strategies.
Aim of the study was to investigate the roles and interaction mechanisms of RAB40C and SNX9 in prostate adenocarcinoma (PRAD) progression and their impact on the Hippo signaling pathway. PRAD is a significant health concern, and understanding the molecular underpinnings is essential for its effective management. Objective of this study was to identify key genes and pathways involved in PRAD using weighted gene co-expression network analysis (WGCNA) and determine the functional implications of RAB40C and its relationship with SNX9.
Material and Methods:
WGCNA was used to chart gene co-expression patterns in PRAD. Functional enrichment analyses of significant modules were performed, and prognostic insights were derived through differential gene expression analysis. The interaction between RAB40C and SNX9 was elucidated using various in vitro assays and databases.
Results:
WGCNA identified a module (MEblue) highly correlated with PRAD. The hub gene was revealed, with RAB40C being central to PRAD progression. The knockdown of RAB40C inhibited PRAD cell proliferation, migration, and invasion. SNX9 was identified as a substrate protein interacting with RAB40C. The silencing of RAB40C led to increased SNX9 expression, suggesting an inverse regulatory relationship. RAB40C promoted SNX9 degradation via the ubiquitin-proteasome pathway. Silencing RAB40C reduced PRAD cell proliferation, migration, and invasion, effects that were counteracted by simultaneous SNX9 suppression. The interaction between RAB40C and SNX9 influenced target proteins of the Hippo signaling pathway.
Conclusions:
RAB40C is essential for the progression of PRAD, partly through modulating SNX9 levels and the Hippo signaling pathway. This interplay offers novel insights for PRAD therapeutic strategies.
REFERENCES (42)
1.
Madueke I, Hu WY, Hu D, et al. (2019): The role of WNT10B in normal prostate gland development and prostate cancer. Prostate 79: 1692-1704.
2.
Pernar CH, Ebot EM, Wilson KM, Mucci LA (2018): The epidemiology of prostate cancer. Cold Spring Harbor Perspect Med 8: a030361.
3.
Smith MR, Saad F, Chowdhury S, et al. (2021): Apalutamide and overall survival in prostate cancer. Eur Urol 79: 150-158.
4.
Kucera R, Pecen L, Topolcan O, et al. (2020): Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions. EPMA J 11: 399-418.
5.
Kumar S, Singh R, Malik S, et al. (2018): Prostate cancer health disparities: an immuno-biological perspective. Cancer Lett 414: 153-165.
6.
Gandhi J, Afridi A, Vatsia S, et al. (2018): The molecular biology of prostate cancer: current understanding and clinical implications. Prostate Cancer Prostatic Dis 21: 22-36.
7.
Matsushita M, Fujita K, Nonomura N (2020): Influence of diet and nutrition on prostate cancer. Int J Mol Sci 21: 1447.
8.
Gillessen S, Attard G, Beer TM, et al. (2020): Management of patients with advanced prostate cancer: report of the advanced prostate cancer consensus conference 2019. Eur Urol 77: 508-547.
9.
Choi E, Buie J, Camacho J, et al. (2022): Evolution of androgen deprivation therapy (ADT) and its new emerging modalities in prostate cancer: an update for practicing urologists, clinicians and medical providers. Res Rep Urol 2022: 87-108.
10.
Coppola U, Ristoratore F, Albalat R, D’Aniello S (2019): The evolutionary landscape of the Rab family in chordates. Cell Mol Life Sci 76: 4117-4130.
11.
Qin X, Wang J, Wang X, et al. (2017): Targeting Rabs as a novel therapeutic strategy for cancer therapy. Drug discovery today. Drug Discov Today 22: 1139-1147.
12.
Duncan ED, Lencer E, Linklater E, Prekeris R (2021): Methods to study the unique SOCS box domain of the Rab40 small GTPase subfamily. In: Rab GTPases: Methods and Protocols; 163-179.
13.
Shahabi A, Naghili B, Ansarin K, Zarghami N (2019): The relationship between microRNAs and Rab family GTPases in human cancers. J Cell Physiol 234: 12341-12352.
14.
Zhao Y, Xiong X, Sun Y (2020): Cullin-RING Ligase 5: Functional characterization and its role in human cancers. Semin Cancer Biol 67: 61-79.
15.
Wu H, Dong X, Liao L, Huang L (2022): An integrative analysis identifying RAB40C as an oncogenic immune protein and prognostic marker of lung squamous cell carcinoma. Pharmacogenom Pers Med 15: 525-537.
16.
Khakpour G, Noruzinia M, Izadi P, et al. (2017): Methylomics of breast cancer: seeking epimarkers in peripheral blood of young subjects. Tumour Biol 39: 1010428317695040.
17.
Wang X, Li Y, He M, et al. (2022): UbiBrowser 2.0: a comprehensive resource for proteome-wide known and predicted ubiquitin ligase/deubiquitinase–substrate interactions in eukaryotic species. Nucleic Acids Res 50: D719-D728.
18.
Mbaeri T, Nwadi U, Abiahu J, et al. (2018): Correlation between prostate specific antigen, digital rectal examination and histology in patients with prostate cancer. Niger J Med 27: 212-218.
19.
Okpua NC, Okekpa SI, Njaka S, Emeh AN (2021): Clinical diagnosis of prostate cancer using digital rectal examination and prostate-specific antigen tests: a systematic review and meta-analysis of sensitivity and specificity. Afr J Urol 27: 1-9.
20.
Kuppusamy S, Quek KF, Rajandram R, et al. (2018): Revisiting prostate specific antigen density (PSAD): a prospective analysis in predicting the histology of prostate biopsy. Int J Clin Exp Med 11: 3873-3879.
21.
Duffy MJ (2020): Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med 58: 326-339.
22.
Garrido MM, Marta JC, Bernardino RM, et al. (2022): The Percentage of [–2] pro-prostate-specific antigen and the prostate health index outperform prostate-specific antigen and the percentage of free prostate-specific antigen in the detection of clinically significant prostate cancer and can be used as reflex tests. Arch Pathol Lab Med 146: 691-700.
23.
Munteanu VC, Munteanu RA, Gulei D, et al. (2020): PSA based biomarkers, imagistic techniques and combined tests for a better diagnostic of localized prostate cancer. Diagnostics 10: 806.
24.
Shahryari A, Jazi MS, Mohammadi S, et al. (2019): Development and clinical translation of approved gene therapy products for genetic disorders. Front Genet 10: 868.
25.
Armstrong AJ, Lin P, Tombal B, et al. (2020): Five-year survival prediction and safety outcomes with enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer from the PREVAIL trial. Eur Urol 78: 347-357.
26.
Hassanipour S, Delam H, Arab-Zozani M, et al. (2020): Survival rate of prostate cancer in Asian countries: a systematic review and meta-analysis. Ann Glob Health 86: 1.
27.
Schroeder A, Herrmann A, Cherryholmes G, et al. (2014): Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res 74: 1227-1237.
28.
Qiao J, Kang J, Ishola TA, et al. (2008): Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma. Proc Natl Acad Sci USA 105: 12891-12896.
29.
Day JP, Whiteley E, Freeley M, et al. (2018): RAB40C regulates RACK1 stability via the ubiquitin–proteasome system. Future Sci OA 4: FSO317.
30.
Neumann AJ, Prekeris R (2023): A Rab-bit hole: Rab40 GTPases as new regulators of the actin cytoskeleton and cell migration. Front Cell Dev Biol 11.
31.
Han KJ, Mikalayeva V, Gerber SA, et al. (2022): Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation. Life Sci Alliance 5: 9.
32.
Linklater ES (2020): Regulation of cancer cell migration and invasion by Rab40b. University of Colorado Denver, Anschutz Medical Campus.
33.
Weidle UH, Birzele F, Auslaender S, Brinkmann U (2021): Down-regulated micrornas in gastric carcinoma may be targets for therapeutic intervention and replacement therapy. Anticancer Res 41: 4185-4202.
34.
Garber JJ, Mallick EM, Scanlon KM, et al. (2018): Attaching-and-effacing pathogens exploit junction regulatory activities of N-WASP and SNX9 to disrupt the intestinal barrier. Cell Mol Gastroenterol Hepatol 5: 273-288.
35.
Blue RE, Curry EG, Engels NM, et al. (2018): How alternative splicing affects membrane-trafficking dynamics. J Cell Sci 131: jcs216465.
36.
Bendris N, Schmid SL (2017): Endocytosis, metastasis and beyond: Multiple facets of SNX9. Trends Cell Biol 27: 189-200.
37.
Tanigawa K, Maekawa M, Kiyoi T, et al. (2019): SNX9 determines the surface levels of integrin 1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9. J Cell Physiol 234: 17280-17294.
38.
Trefny MP, Kirchhammer N, Auf der Maur P, et al. (2023): Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy. Nat Commun 14: 86.
39.
Snigdha K, Gangwani KS, Lapalikar GV, et al. (2019): Hippo signaling in cancer: lessons from Drosophila models. Front Cell Dev Biol 7: 85.
40.
Li FL, Guan KL (2022): The two sides of Hippo pathway in cancer. Semin Cancer Biol 85: 33-42.
41.
Koinis F, Chantzara E, Samarinas M, et al. (2022): Emerging role of YAP and the Hippo pathway in prostate cancer. Biomedicines 10: 2834.
42.
Coffey K (2021): Targeting the Hippo pathway in prostate cancer: what’s new? Cancers 13: 611.
| eISSN: | 1644-4124 |
| ISSN: | 1426-3912 |
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