ABSTRACT
Chromodomain helicase DNA binding protein (CHD) family plays critical roles in regulating gene transcription. The family is linked to cancer disease, but the family member's role in tumorigenesis remains largely unknown. Here, we report that CHD6 is highly expressed in colorectal cancer (CRC). CHD6 knockdown inhibited cancer cell proliferation, migration, invasion, and tumorigenesis. Consistently, Villin-specific Chd6 knockout in mice attenuates cancer formation in AOM/DSS model. We found that aberrant EGF signals promoted the stability of CHD6 by diminishing ubiquitin-mediated degradation. EGF signal inhibits GSK3ß activity, which in turn prevents phosphodegron formation of CHD6, thereby hindering E3 ligase FBXW7-mediated CHD6 ubiquitination and degradation. CHD6's chromatin remodeler activity engages in binding Wnt signaling transcription factor TCF4 to facilitate the transcriptional expression of TMEM65, a mitochondrial inner membrane protein involved in ATP production and mitochondrial dynamics. In addition, Wnt signaling is also an upstream regulator of CHD6. CHD6 promoter contains TCF4 and ß-catenin binding site, and CHD6 can be transcriptionally activated by Wnt ligand to facilitate TMEM65 transcription. Thus CHD6-TMEM65 axis can be regulated by both EGF and Wnt signaling pathways through two different mechanisms. We further illustrate that CHD6-TMEM65 axis is deregulated in cancer and that co-administration of Wnt inhibitor LGK974 and the anti-EGFR monoclonal antibody cetuximab largely restricted the growth of patient-derived xenografts of CRC. Targeting CHD6-TMEM65 axis may be effective for cancer intervention.
ABSTRACT
In the present study, the authors assessed the differences in natural growth rates between skull base and non-skull base meningiomas by meta-analysis. Studies investigating meningioma growth rate were compiled from PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature database, and the China National Knowledge Infrastructure databases. A systematic review and meta-analysis of the collected literature were conducted using Stata 12.0 software. A total of 7 observational cohort studies, including 361 patients with untreated meningiomas, were included in the study. Meta-analysis showed that the weighted mean difference for absolute growth rate (years), relative growth rate (years), and doubling time (month) were 0.42 (95% confidence interval [CI]: 0.20-0.64, Pâ<.0001), 1.08 (95%CI: 0.85-1.32, Pâ<.0001), and -0.56 [95%CI: (-0.78)-(-0.33), Pâ<.0001)] respectively. These findings indicate that the natural growth rate of skull base meningioma is less than that of non-skull base meningioma.
