Dataset Information

Deciphering the clinical significance and kinase functions of GSK3α in colon cancer by proteomics and phosphoproteomics

ABSTRACT: In this study, paired tumors and distant normal tissues (DNTs) collected from 78 treatment-naïve colon cancer patients were subjected to tandem mass tag (TMT)-based proteomics. We found that the expression of GSK3α, but not GSK3β, was significantly correlated with the overall survival (OS) of colon cancer patients in 3 independent cohorts. To decipher the roles of GSK3α in colon cancer, we profiled the phosphorylation substrates of GSK3α. Initial in vitro and in vivo phosphoproteomics analyses uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3α but not GSK3β. Notably, the levels of some phosphosites, including HSF1S303p, CANXS583p, MCM2S41p, POGZS425p, SRRM2T983p and PRPF4BS431p, were significantly correlated with the OS of colon cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1 and STAU1, that showed strong binding affinity to GSK3α. The tight interaction between THRAP3 and GSK3α was verified by biochemical experiments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253 and S682 is specifically mediated by GSK3α in vitro and in cell lines. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3α as a kinase but also suggests GSK3α as a promising therapeutic target for colon cancer.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lunzhi Dai

PROVIDER: PXD038830 | iProX | Fri Mar 03 00:00:00 GMT 2023

REPOSITORIES: iProX

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Deciphering the Clinical Significance and Kinase Functions of GSK3α in Colon Cancer by Proteomics and Phosphoproteomics.

Gao Li L Lu Ying Y Chen Hai-Ning HN Li Zhigui Z Hu Meng M Zhang Rou R Wang Xiuxuan X Xu Zhiqiang Z Gong Yanqiu Y Wang Rui R Du Dan D Hai Shan S Li Shuangqing S Su Dan D Li Yuan Y Xu Heng H Zhou Zong-Guang ZG Dai Lunzhi L

Molecular & cellular proteomics : MCP 20230408 5

GSK3α and GSK3β are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK3β plays important roles in the pathogenesis of cancer, while GSK3α has long been considered a functionally redundant protein of GSK3β. Few studies have specifically investigated the functions of GSK3α. In this study, unexpectedly, we found that the expression of GSK3α, but not GSK3β, was significantly correlated with the overall survival of colon cancer patients in 4 independent cohor ...[more]

PMID: 37031867

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Project description:Background and Aims: Staging inadequately predicts metastatic risk in colon cancer patients. We used a gene expression profile derived from invasive murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify colon cancer patients at risk for recurrence in a phase I, exploratory biomarker study. Methods: 55 colorectal cancer patients from Vanderbilt Medical Center (VMC) were used as the training dataset and 177 patients from the Moffitt Cancer Center were used as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined using comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A recurrence score derived from the biologically based classifier was tested in the Moffitt dataset. Results: A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathological stages and specifically in stage II and stage III patients. The recurrence score was shown to independently predict risk of cancer recurrence and death in both univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk for cancer recurrence (hazard ratio = 4.7 (95% CI=1.566-14.05)). Furthermore, the recurrence score identified stage III patients whose five-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not provide improved survival. Conclusion: Our biologically based gene expression profile yielded a potentially useful classifier to predict cancer recurrence and death independently of conventional measures in colon cancer patients. Experiment Overall Design: Gene expression array differences between highly invasive mouse colon cancer cells and non-invasive colon cancer cells were used to develop a metastasis gene expression profile. It was refined using gene expression data from 55 patient (VMC) samples and trained using 177 patient (Moffitt) samples.

Dataset Information

Deciphering the clinical significance and kinase functions of GSK3α in colon cancer by proteomics and phosphoproteomics

Publications

Deciphering the Clinical Significance and Kinase Functions of GSK3α in Colon Cancer by Proteomics and Phosphoproteomics.

Similar Datasets

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