Sulforaphane targets STAT3-CKMT2-AS1 to suppress gastric cancer via PSMB8 downregulation and AIMP1 stabilization.

[BACKGROUND] Gastric cancer (GC) remains one of the most formidable threats to human health with limited therapeutic options. Sulforaphane (SFN), a natural isothiocyanate, exhibits antitumor activity; however, its molecular mechanisms of action in GC remain unclear.

[PURPOSE] To investigate the mechanism of action of SFN in gastric cancer.

[METHODS] The antitumor effects of SFN were comprehensively assessed in vitro and in vivo, followed by sequencing analysis to identify the targeted lncRNA. Subsequently, the mechanical verification experiments were carried out to determine the upstream and downstream regulatory components involved in the STAT3-CKMT2-AS1 regulatory axis.

[RESULTS] We demonstrated that SFN strongly inhibits GC. SFN downregulated the expression of the lncRNA CKMT2-AS1. Elevated expression levels of CKMT2-AS1 in human GC tissues are correlated with poor patient survival rates. Knockdown of CKMT2-AS1 significantly inhibited GC proliferation and migration both in vivo and in vitro, whereas CKMT2-AS1 overexpression enhanced malignant phenotypes. Mechanistically, we identified STAT3 as the transcriptional activator driving CKMT2-AS1 expression, with SFN directly binding to, and inhibiting, STAT3 phosphorylation to decrease its transcriptional activity. Interestingly, cytoplasmic CKMT2-AS1 competitively adsorbs miR-451a, leading to the expression of PSMB8, ultimately promoting the progression of the malignant phenotype of GC. Moreover, we discovered that CKMT2-AS1 directly binds to the RNA-binding protein (RBP) AIMP1, promoting ubiquitination-mediated degradation of AIMP1 protein via the proteasomal pathway. The highly expressed AIMP1 protein, in turn, inhibits the phosphorylation of the PI3K/AKT signaling pathway, which is hyperactivated in virtually all solid tumors.

[CONCLUSION] Our findings not only elucidate a novel SFN-mediated tumor-suppressive mechanism via the STAT3/CKMT2-AS1 regulatory axis, but also validate CKMT2-AS1 as a promising therapeutic target for GC intervention.