Cofilin/RhoA and CREB synergistically promote invasion and migration of polyploid giant cancer cells in colorectal cancer.

Abstract

Colorectal cancer (CRC) is associated with high mortality and poor survival. Polyploid giant cancer cells (PGCCs) are a subset of cancer cells that drive tumor initiation and progression. In this study, high-concentration CoCl₂ treatment was used to induce Hct116 and LoVo cells to form PGCCs with daughter cells (PDCs), which exhibited enhanced invasion and migration capabilities. Cofilin expression was elevated in PDCs compared to that in the control cells. Mechanistically, the small ubiquitin-like modification (SUMOylation) of cofilin promoted its nuclear translocation and contributed to the aggressive phenotype of PDCs, with lysine 132 being identified as the key modification site mediated by tripartite motif-containing 28 (TRIM28). In addition, TRIM28 directly interacted with cofilin and inhibited its degradation, thereby increasing its stability. Nuclear cofilin facilitated RNA polymerase II-dependent upregulation of Ras homolog family member A (RhoA) transcription. RhoA enhanced nuclear accumulation of phosphorylated CREB (p-CREB), which further promoted cofilin transcription by binding to its promoter region. Cofilin knockdown inhibited the growth of xenograft tumors derived from Hct116 and LoVo PDCs. Regression analysis revealed that cofilin overexpression was associated with aggressive clinicopathological features in patients with CRC, although it did not significantly correlate with overall survival. Collectively, these findings revealed that cofilin is regulated by TRIM28-mediated SUMOylation and suggested that targeting the cofilin/RhoA/CREB axis may represent a promising therapeutic strategy for CRC.