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.
Highlights
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and accounted for 1.8 million new cases and 540 000 deaths worldwide in 2018 [1]
Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is upregulated in metastatic colorectal cancer (mCRC) and associated with poor prognosis in CRC patients To understand the role of BCKDK in CRC progression, the mRNA expression level of BCKDK was first analyzed by using the Oncomine database
Previous studies have shown that branched-chain amino acids (BCAAs) are strongly associated with human metabolic diseases and tumor: elevated plasma BCAAs levels are strongly associated with type 2 diabetes [47] and a high incidence of pancreatic cancer [48]; a BCAAs-rich diet is beneficial for the treatment of hepatocellular carcinoma and liver cirrhosis [49]; and dietary leucine supplements promote the tumorigenesis of pancreatic cancer [50]
Summary
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and accounted for 1.8 million new cases and 540 000 deaths worldwide in 2018 [1]. MEK was indicated to bind with and phosphorylated by BCKDK at the S221 site, thereby activating tumor cell proliferation [25]. Src signaling pathways play a crucial role in regulating tumor cell proliferation, survival, tumor angiogenesis [28], epithelial mesenchymal transition (EMT) [29], migration, adhesion, and metastasis [30]. In human CRC, elevated Src activity is considered an independent indicator of poor clinical prognosis in patients [31]. As an upstream regulator of BCKDK, inhibition of Src downregulated the phosphorylation of BCKDK, suggesting the necessary role of Src in maintaining the prometastatic function of BCKDK Taken together, these results demonstrate the significance of the Src/BCKDK axis in human CRC and provide a promising novel target for mCRC targeted therapy
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