ITF2357 exerts anti‑tumor activity in colorectal cancer via the miR‑1938/ADAM12 axis.

PURPOSE: Histone deacetylase inhibitors (HDACi) have emerged as promising anticancer agents. This study aimed to investigate the antitumor efficacy and molecular mechanism of ITF2357 (Givinostat), a novel HDACi, in colorectal cancer (CRC).

METHODS

In vitro, CT26 cell viability, proliferation, colony formation, and cell cycle distribution were assessed. In vivo, a subcutaneous CT26 tumor model was established in female BALB/c mice to evaluate the antitumor effect of ITF2357. Multi-omics analysis (miRNA-seq, mRNA-seq, ATAC-seq) was performed to identify key regulatory molecules, followed by qRT-PCR, dual-luciferase reporter, and knockdown assays for mechanistic validation.

RESULTS

ITF2357 significantly inhibited CT26 cell proliferation and induced G0/G1 phase arrest. In vivo, ITF2357 suppressed tumor growth without affecting body weight or liver and kidney tissues, suggesting no obvious systemic toxicity. Multi-omics analysis revealed that ITF2357 upregulated miR-1938, which directly targeted the 3'-UTR of ADAM12. ADAM12 knockdown phenocopied the anti-proliferative and cell cycle arrest effects of ITF2357. Clinically, high ADAM12 expression correlated with poor prognosis in CRC patients.

CONCLUSION

ITF2357 exerts anti-CRC activity by upregulating miR-1938 to suppress ADAM12, leading to cell cycle arrest. These findings provide new mechanistic insights into the anti-CRC effects of ITF2357 and establish a foundation for exploring its therapeutic potential in CRC.