Phosphorylation of BCKDK of BCAA Catabolism at Y246 by Src Promotes Metastasis of Colorectal Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2020 Apr 3

PMID 32238881

Citations 34

Authors

Qin Tian

Ping Yuan

Chuntao Quan

Mingyang Li

Juanjuan Xiao

Lu Zhang

Hui Lu

Tengfei Ma

Ling Zou

Fei Wang

Peipei Xue

Xiaofang Ni

Wei Wang

Lin Liu

Zhe Wang

Feng Zhu

Qiuhong Duan

Affiliations

Soon will be listed here.

Abstract

Branched-chain α-keto acid dehydrogenase kinase (BCKDK), the key enzyme of branched-chain amino acids (BCAAs) metabolism, has been reported to promote colorectal cancer (CRC) tumorigenesis by upregulating the MEK-ERK signaling pathway. However, the profile of BCKDK in metastatic colorectal cancer (mCRC) remains unknown. Here, we report a novel role of BCKDK in mCRC. BCKDK is upregulated in CRC tissues. Increased BCKDK expression was associated with metastasis and poor clinical prognosis in CRC patients. Knockdown of BCKDK decreased CRC cell migration and invasion ex vivo, and lung metastasis in vivo. BCKDK promoted the epithelial mesenchymal transition (EMT) program, by decreasing the expression of E-cadherin, epithelial marker, and increasing the expression of N-cadherin and Vimentin, which are mesenchymal markers. Moreover, BCKDK-knockdown experiments in combination with phosphoproteomics analysis revealed the potent role of BCKDK in modulating multiple signal transduction pathways, including EMT and metastasis. Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. In summary, the identification of BCKDK as a novel prometastatic factor in human CRC will be beneficial for further diagnostic biomarker studies and suggests novel targeting opportunities.

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