AGEs promote the metastasis of colorectal cancer cells via centrosome amplification by KLF5–CEP57L1 axis

TL;DR

AGEs, linked to diabetes, promote colorectal cancer metastasis by causing centrosome amplification through a specific protein pathway.

Contribution

This study reveals a novel molecular mechanism linking diabetes to cancer metastasis via the KLF5–CEP57L1 axis and centrosome amplification.

Findings

AGEs increase centrosome amplification and metastasis in colorectal cancer cells.

KLF5, KLHL13, and CUL3 are downregulated in cancer tissues, especially in diabetic patients.

Reduced levels of KLF5, KLHL13, and CUL3 correlate with poorer survival in cancer patients.

Abstract

Despite the accumulating evidence that diabetes and centrosome amplification (CA) are both associated with cancer cell metastasis, in particular the observations in gene-edited animal models, their relationships and the underlying molecular mechanisms remain unknown under pathophysiological conditions. In the present study, we examined if CA could serve as a biological link between diabetes and metastasis. Our results showed that, in vitro, advanced glycation end products (AGEs) promoted CA, migration, and invasion of HCT116 colorectal cancer cells, with the highest CA level in the migrated cell fraction, and upregulated FAM111B, which promoted epithelial–mesenchymal transition. Upon AGE treatment, Krüppel-like factor 5 (KLF5), Kelch-like (KLHL)13, and Cullin3 (CUL3) were downregulated and CEP57L1 was upregulated, respectively; the latter was due to an insufficient KLF5-mediated transcription of KLHL13 and CUL3 and therefore compromised protein ubiquitination degradation. Importantly, AGEs promoted CEP57L1-dependent metastasis of the cancer cells in a mouse model. In a cohort of cancer patients, KLF5, KLHL13, and CUL3 levels were lower, but CA and CEP57L1 were higher in cancer tissues, compared with noncancerous counterparts, which were more obvious in those with diabetes. Decreased KLF5, KLHL13, and CUL3, together, were associated with poorer survival. In conclusion, it is suggested that AGEs promote the cancer cell metastasis via CA by KLF5–CEP57L1 axis, which underlies diabetes-promoted cancer metastasis.

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