Hypoxia Affects Mitochondrial Stress and Facilitates Tumor Metastasis of Colorectal Cancer Through Slug SUMOylation

Abstract

Background: Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored.

Objective: Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC.

Methods: Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO- 1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay.

Results: Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment.

Conclusion: Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation.

Keywords: CRC; colorectal cancer; hypoxia; mitochondrial stress; slug SUMOylation; tumor metastasis..