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Sulforaphane targets STAT3-CKMT2-AS1 to suppress gastric cancer via PSMB8 downregulation and AIMP1 stabilization
Peng-Tao Liu1, Bo Zhang2, Ce Liu2
1State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China; State Key Laboratory Incubation Base for Conservation and Utilization of Bioresource in Tarim Basin, College of Life Sciences and Technology, Tarim University, Alar, China.
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.
Insights
Sulforaphane (SFN) inhibits gastric cancer (GC) by targeting the STAT3/CKMT2-AS1 pathway. This study reveals SFN
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gastric cancer (GC) presents a significant global health challenge with limited treatment avenues.
- Sulforaphane (SFN), a natural compound, shows potential antitumor effects, but its specific mechanisms in GC are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which SFN exerts its anti-gastric cancer effects.
- To identify and characterize the key molecular players involved in SFN's action against GC.
Main Methods:
- In vitro and in vivo studies assessed SFN's antitumor efficacy.
- Sequencing identified the long non-coding RNA (lncRNA) CKMT2-AS1 as a target.
- Experiments validated the STAT3-CKMT2-AS1 regulatory axis.
Main Results:
- SFN significantly inhibits GC progression and metastasis.
- SFN downregulates the oncogenic lncRNA CKMT2-AS1, whose high expression correlates with poor prognosis.
- SFN disrupts the STAT3/CKMT2-AS1 axis by inhibiting STAT3 phosphorylation and affecting downstream targets like miR-451a, PSMB8, AIMP1, and the PI3K/AKT pathway.
Conclusions:
- A novel SFN-driven tumor-suppressive mechanism involving the STAT3/CKMT2-AS1 pathway is elucidated.
- CKMT2-AS1 emerges as a potential therapeutic target for gastric cancer intervention.
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