RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinoma
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Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates β-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the β-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/β-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy.
Abstract
Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates β-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the β-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/β-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy.
참고문헌 (39)
- Llovet, J. M., "Hepatocellular carcinoma", Nat. Rev. Dis. Primers, 7, pp.6~ (2021)
- Villanueva, A., "Hepatocellular carcinoma", New England J. Med, 380, pp.1450~1462 (2019)
- Craig, A. J., "Tumour evolution in hepatocellular carcinoma", Nat. Rev. Gastroenterol. Hepatol, 17, pp.139~152 (2020)
- Marrero, J. A., "Diagnosis, staging, and management of hepatocellular car cinoma : 2018 Practice Guidance by the American Association for the Study of Liver Diseases", Hepatology, 68, pp.723~750 (2018)
- Masuho, I., "A global map of G protein signaling regulation by RGS proteins", Cell, 183, pp.503~521 (2020)
- Ahlers, K. E., "RGS6 as a novel therapeutic target in CNS diseases and cancer", AAPS J, 18, pp.560~572 (2016)
- Riddle, E. L., "Multi-tasking RGS proteins in the heart: the next therapeutic target?", Circ. Res, 96, pp.401~411 (2005)
- Huang, D., "Targeting regulator of G protein signaling 1 in tumor-specific T cells enhances their trafficking to breast cancer", Nat. Immunol, 22, pp.865~879 (2021)
- Berman, D. M., "GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits", Cell, 86, pp.445~452 (1996)
- Lou, X., "GIPC and GAIP form a complex with TrkA : a putative link between G protein and receptor tyrosine kinase pathways", Mol. Biol. Cell, 12, pp.615~627 (2001)
- Tso, P. H., "RGS19 stimulates cell proliferation by deregulating cell cycle control and enhancing Akt signaling", Cancer Lett, 309, pp.199~208 (2011)
- Hu, Y., "Identification of a five-gene signature of the RGS gene family with prognostic value in ovarian cancer", Genomics, 113, pp.2134~2144 (2021)
- Hu, D., "Development of an autophagy-related gene expression signature for prognosis prediction in prostate cancer patients", J. Transl. Med, 18, pp.160~ (2020)
- Liu, Y., "Genome-wide screening for the G-protein-coupled receptor(GPCR)pathway-related therapeutic gene RGS19(regulator of G protein signaling 19)in bladder cancer", Bioengineered, 12, pp.5892~5903 (2021)
- Zhong, Y., "MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly", Cell Death Differ, 28, pp.3251~3269 (2021)
- Lin, X., "Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma", Signal Transduct. Targeted Therapy, 5, pp.13~ (2020)
- Singh, S. K., "MYH9 suppresses melanoma tumorigenesis, metastasis and regulates tumor microenvironment", Med. Oncol. (Northwood, London, England), 37, pp.88~ (2020)
- Zhou, P., "NMIIA promotes tumor growth and metastasis by activating the Wnt", β-catenin signaling pathway and EMT in pancreatic cancer, 2019, pp.38, 5500~5515
- Ye, G., "Nuclear MYH9-induced CTNNB1 transcription, targeted by staur osporin, promotes gastric cancer cell anoikis resistance and metastasis", Ther anostics, 10, pp.7545~7560 (2020)
- Thompson, M. D., "WNT", beta-catenin signaling in liver health and disease, 2007, pp.45, 1298~1305
- Monga, S. P., "β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis", Gastroenterology, 148, pp.1294~1310 (2015)
- Vlad, A., "The first five years of the Wnt targetome", Cell. Signall, 20, pp.795~802 (2008)
- Perugorria, M. J., "Wnt-β-catenin signalling in liver development, health and disease", Nat. Rev. Gastroenterol. Hepatol, 16, pp.121~136 (2019)
- Dang, C. V., "c-Myc target genes involved in cell growth, apoptosis, and metabo lism", Mol. Cell. Biol, 19, pp.1~11 (1999)
- Casey, S. C., "The MYC oncogene is a global regulator of the immune response", Blood, 131, pp.2007~2015 (2018)
- Casey, S. C., "MYC : master regulator of immune privilege", Trends Immunol, 38, pp.298~305 (2017)
- "Comprehensive and integrative genomic characterization of hepatocellular car cinoma", Cell, 169, pp.1327~1341 (2017)[DOI]
- Roessler, S., "A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients", Cancer Res, 70, pp.10202~10212 (2010)
- Ogier-Denis, E., "Erk1", 2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells, 2000, pp.275, 39090~39095
- Dasgupta, S., "RGS5-TGFβ-Smad2", 3 axis switches pro-to anti-apoptotic sig naling in tumor-residing pericytes, assisting tumor growth, 2021, pp.28, 3052~3076
- Li, C., "The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS", Science (New York, N.Y.), 374, pp.197~201 (2021)
- Cho, J., "RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse", J. Clin. Invest, 131 (2021)[DOI]
- Gao, S., "TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β", β-catenin signalling, 2022, pp.13, 2792~
- Hu, S., "Glycoprotein PTGDS promotes tumorigenesis of diffuse large B-cell lymphoma by MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling", Cell Death Differ, 29, pp.642~656 (2022)
- Li, Y., "circ-EIF6 encodes EIF6-224aa to promote TNBC progression via sta bilizing MYH9 and activating the Wnt", beta-catenin pathway, 2022, pp.30, 415~430
- Mahlokozera, T., "Competitive binding of E3 ligases TRIM26 and WWP2controls SOX2 in glioblastoma", Nat. Commun, 12, pp.6321~ (2021)
- Liu, L., "An RFC4", Notch1 signaling feedback loop promotes NSCLC metastasis and stemness, 2021, pp.12, 2693~
- Shroff, E. H., "MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism", Proc. Natl Acad. Sci. USA, 112, pp.6539~6544 (2015)
- Sodir, N. M., "MYC instructs and maintains pancreatic adenocarcinoma phenotype", Cancer Discov, 10, pp.588~607 (2020)
