Dataset Information

Elf3 drives ?-catenin transactivation and associates with poor prognosis in colorectal cancer.

ABSTRACT: Aberrant regulation of the Wnt/?-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring ?-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for ?-catenin protein turnover, little is known about the regulation of ?-catenin in transcriptional level. Here we show that Elf3, a member of the E-twenty-six family of transcription factors, drives ?-catenin transactivation and associates with poor survival of colorectal cancer (CRC) patients. We first found recurrent amplification and upregulation of Elf3 in CRC tissues, and further Gene Set Enrichment Analysis identified significant association between Elf3 expression and activity of WNT/?-catenin pathway. Chromatin immunoprecipitation and electrophoretic mobility shift assay consistently revealed that Elf3 binds to and transactivates ?-catenin promoter. Ectopic expression of Elf3 induces accumulation of ?-catenin in both nucleus and cytoplasm, causing subsequent upregulation of several effector genes including c-Myc, VEGF, CCND1, MMP-7 and c-Jun. Suppressing Elf3 in CRC cells attenuates ?-catenin signaling and decreases cell proliferation, migration and survival. Targeting Elf3 in xenograft tumors suppressed tumor progression in vivo. Taken together, our data identify Elf3 as a pivotal driver for ?-catenin signaling in CRC, and highlight potential prognostic and therapeutic significance of Elf3 in CRC.

SUBMITTER: Wang JL

PROVIDER: S-EPMC4047871 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer.

Wang J-L JL Chen Z-F ZF Chen H-M HM Wang M-Y MY Kong X X Wang Y-C YC Sun T-T TT Hong J J Zou W W Xu J J Fang J-Y JY

Cell death & disease 20140529

Aberrant regulation of the Wnt/β-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring β-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for β-catenin protein turnover, little is known about the regulation of β-catenin in transcriptional level. Here we show that Elf3, a member of the E-twenty-six family of transcription factors, drives β-catenin transactivation and associat ...[more]

PMID: 24874735

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Project description:Introduction: Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in serine-glycine metabolism to drive cancer cell proliferation. However, the nonmetabolic function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Methods: SHMT2 expression in human CRC cells was identified by western blot and immunofluorescence assay. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown or overexpression were explored through in vitro and in vivo assays. Immunofluorescence, mRNA-seq, co-immunoprecipitation, chromatin immunoprecipitation-qPCR and immunohistochemistry assays were used to investigate the underlying mechanisms behind the SHMT2 nonmetabolic function. Results: We demonstrated that SHMT2 was distributed in the cytoplasm and nucleus of human CRC cells. SHMT2 knockdown resulted in the significant inhibition of CRC cell proliferation, which was not restored by serine, glycine, or formate supplementation. The invasion and migration of CRC cells were suppressed after SHMT2 knockdown. Mechanistically, SHMT2 interacted with β-catenin in the cytoplasm. This interaction inhibited the ubiquitylation-mediated degradation of β-catenin and subsequently modulated the expression of its target genes, leading to the promotion of CRC cell proliferation and metastasis. Notably, the lysine 64 residue on SHMT2 (SHMT2K64) mediated its interaction with β-catenin. Moreover, transcription factor TCF4 interacted with β-catenin, which in turn increased SHMT2 expression, forming an SHMT2/β-catenin positive feedback loop. In vivo xenograft experiments confirmed that SHMT2 promoted the growth and metastasis of CRC cells. Finally, the level of SHMT2 was found to be significantly increased in human CRC tissues. The SHMT2 level was correlated with an increased level of β-catenin, associated with CRC progression and predicted poor patient survival. Conclusion: Taken together, our findings reveal a novel nonmetabolic function of SHMT2 in which it stabilizes β-catenin to prevent its ubiquitylation-mediated degradation and provide a potential therapeutic strategy for CRC therapy.

Dataset Information

Elf3 drives ?-catenin transactivation and associates with poor prognosis in colorectal cancer.

Publications

Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer.

Similar Datasets

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