DNA Damage-Mediated c-Myc Degradation Requires 14-3-3 Sigma

Biomarkers for predicting chemotherapy response are important to treatment of colorectal cancer (CRC) patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biological consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here we report that CRY2 is overexpressed in chemoresistant CRC samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cell. We also identify FBXW7 as a novel E3 ubiquitin ligase for targeting CRY2 through proteasomal degradation. Mechanistic studies show that CRY2 is regulated by FBXW7, in which FBXW7 binds directly to phosphorylated Thr300 of CRY2. Furthermore, FBXW7 expression leads to degradation of CRY2 through enhancing CRY2 ubiquitination and accelerating CRY2’s turnover rate. High expressed FBXW7 downregulates CRY2 and increases colorectal cancer cells sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in CRC patient samples. Also, low FBXW7 expression is correlated with poor patient survival. Taken together, our findings indicate that the upregulation of CRY2 caused by downregulation of FBXW7 may be a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.

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“…Turnover rate was analyzed as previously described (46) (47, 48). Then cycloheximide was added into the media at 60ug/ml of final concentration.…”

Section: Methodsmentioning

confidence: 99%

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Fang

Yang

Zhou

et al. 2015

Molecular Cancer Therapeutics

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“…[43][44][45] Basically, indicated cells cotransfected with indicated plasmids were used for the experiments. At 24 h post-transfection, cells were treated with 50 mg/ml of MG132 for 6 h. The ubiquitinated proteins were immunoprecipitated with anti-Flag or antip27.…”

Section: Ubiquitination Assaymentioning

confidence: 99%

“…43,44,46 The cells were transfected with the indicated plasmids and incubated at 37 C with 5% (vol/vol) CO2 for 24 h. Then cycloheximide was added into the media to a final concentration of 100 mg/ml. The cells were harvested at the indicated times after CHX treatment.…”

Section: Ubiquitination Assaymentioning

confidence: 99%

Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis

et al. 2015

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The COP9 signalosome subunit 6 (CSN6), which is involved in ubiquitin-mediated protein degradation, is overexpressed in many types of cancer. CSN6 is critical in causing p53 degradation and malignancy, but its target in cell cycle progression is not fully characterized. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase associating with COP9 signalosome to regulate important target proteins for cell growth. p27 is a critical G1 CDK inhibitor involved in cell cycle regulation, but its upstream regulators are not fully characterized. Here, we show that the CSN6-COP1 link is regulating p27(Kip1) stability, and that COP1 is a negative regulator of p27(Kip1). Ectopic expression of CSN6 can decrease the expression of p27(Kip1), while CSN6 knockdown leads to p27(Kip1) stabilization. Mechanistic studies show that CSN6 interacts with p27(Kip1) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on the nuclear export of p27(Kip1), which is regulated through COP1 nuclear exporting signal. COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. Importantly, the negative impact of COP1 on p27 stability contributes to elevating expression of genes that are suppressed through p27 mediation. Kaplan-Meier analysis of tumor samples demonstrates that high COP1 expression was associated with poor overall survival. These data suggest that tumors with CSN6/COP1 deregulation may have growth advantage by regulating p27 degradation and subsequent impact on p27 targeted genes.

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“…12,13 It is important to note that c-Myc activates cell phase and facilitates the gene expression of cdc25A, CDK4, and Cyclin D1, 14 etc. On the other hand, it inhibits gene transcription of p15, p21, and p27, which are CDK inhibitors and negative regulators of cell cycle progression, thereby facilitating cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients

Bai

Xia

et al. 2014

Cell Cycle

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DNA Damage-Mediated c-Myc Degradation Requires 14-3-3 Sigma

Cited by 14 publications

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Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis

Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients

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DNA Damage-Mediated c-Myc Degradation Requires 14-3-3 Sigma

Cited by 14 publications

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Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Regulating the stability and localization of CDK inhibitor p27Kip1 via CSN6-COP1 axis

Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients

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Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis