UHMK1 Dependent Phosphorylation of Cajal Body Protein Coilin Altered 5-FU Sensitivity in Colon Cancer Cells

Abstract Background: Resistance to 5-fluorouracil (5-FU) in chemotherapy and recurrence of colorectal tumors is a serious problem to be resolved for the improvement of clinical outcomes.Methods: In the present study, the effects of conditioned medium (CM) derived from 5-FU-resistant HCT-8/FU on cell functions were evaluated. The methods of immunofluorescence and RNA-seq analyses were used to investigate the molecular mechanism underlining the roles of CM from resistant cells.Results: we found that CM derived from 5-FU-resistant HCT-8/FU was able to reduce 5-FU chemosensitivity of HCT-8 colon cancer cells, with correlating changes in the number and morphology of the Cajal bodies (CBs) as observable nuclear structures. We identified UHMK1 was able to change the disassembly and reassembly of CBs regulated by the phosphorylation of coilin, a major component of CBs, and subsequently resulted in a large number of variations of RNA alternative splicing, affecting the cell survival following 5-FU treatment through changes in intracellular phenotype and transmitted preadaptive signals to adjacent cells in tumor microenvironment (TME).Conclusion: Our finding provided evidence to demonstrate CBs of their disassembling/reassembling dynamics to indicate drug sensitivity or resistance in tumor cells in response to stress signal. The results also suggested that UHMK1 could be an important factor to maintain CB structure and morphology with its possible roles in the regulation of splicing events, especially when cells exposed to cytotoxic drugs.