Effects of p53 on the Regulation of Carbonic Anhydrase 8 in Human Colorectal Cancer Cells: Interaction Between p53 and Sp1

Abstract

Colorectal cancer ranks among the most common malignancies worldwide. Our previous study indicated Carbonic anhydrase 8 (CA8) is linked to cell proliferation and mobility in colon cancer cells. In the present study, we observed a significant increase in the expression of mutant p53 R273H/P309S in colon cancer cell lines (SW480 and SW620) with stably downregulated CA8. P53, a well-known tumor suppressor gene, is frequently mutated in cancer cells, leading to poor prognosis and drug resistance. Although p53 acts as a transcription factor, the increased mutant p53 did not activate downstream target molecules, suggesting activation defects of mutant p53 R273H/P309S. Furthermore, transient downregulation of CA8 did not alter p53 expression, indicating that the observed increase in mutant p53 in stable cells may be a compensatory effect for cell survival. Given that p53 shares similar consensus sequences at GC-boxes with specific protein 1 (Sp1), a predominant transcription factor for CA8 regulation, we examined the relationship between CA8, p53 and Sp1 in HCT116 and SW620 cells harboring wild-type (WT) or mutant p53, respectively. Notably, transient downregulation of p53 or Sp1 led to a significant decrease in CA8 at both mRNA and protein levels in HCT116 and SW620 cells. Additionally, immunoprecipitation results revealed a protein-protein interaction between Sp1 and p53, suggesting that their interaction may be involved in the regulation of CA8 expression. Although the precise mechanism by which Sp1 and p53 regulate CA8 expression remains unclear, we are the first to report that both Sp1 and p53 are involved in the regulation of the novel hCA8 gene. By further unraveling the interplay among CA8, p53, and Sp1, we hope to pave the way for new therapeutic approaches in colon cancer treatment.