Kruppel-like factor 5 enhances proliferation, lipid droplet formation and oxaliplatin resistance in colorectal cancer by promoting fatty acid binding protein 6 transcription.

Abstract

Oxaliplatin (OXA) is a standard agent for colorectal cancer (CRC) adjuvant chemotherapy. However, acquired and intrinsic OXA resistance is a primary challenge for CRC treatment. This study investigates the function of the Kruppel-like factor 5/fatty acid binding proteins 6 (KLF5/FABP6) axis in CRC proliferation, lipid droplet formation and OXA resistance. OXA-resistant CRC cell lines were constructed, and FABP6 and KLF5 expression was assessed in parental and OXA-resistant CRC cells. Subsequent to gain- and loss-of-function experiments, CRC cell proliferation was assessed by cell counting kit-8 (CCK-8) and clone formation assays, the intracellular lipid synthesis by oil red O staining and the protein expression of lipid metabolism genes by western blot. OXA resistance of CRC cells was assessed by CCK-8 assay. The binding of KLF5 to FABP6 was analyzed by the dual-luciferase reporter and ChIP assays. A tumorigenicity assay in nude mice was adopted to examine the impact of KLF5 on CRC tumor growth and OXA resistance in vivo . FABP6 and KLF5 expression was high in CRC cell lines. Downregulation of FABP6 or KLF5 restrained CRC cell proliferation and lipid droplet formation in vitro . FABP6 and KLF5 expression was elevated in OXA-resistant CRC cells. Downregulation of FABP6 or KLF5 repressed the OXA resistance of OXA-resistant CRC cells. Mechanistically, KLF5 facilitated the transcription of FABP6. FABP6 overexpression counteracted the suppressive effects of KLF5 downregulation on CRC cell growth, lipid droplet formation and OXA resistance. KLF5 downregulation restrained CRC tumor growth and OXA resistance in vivo . In conclusion, KLF5 knockdown reduced FABP6 transcription to protect against proliferation, lipid droplet formation and OXA resistance in CRC.