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Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

ABSTRACT: In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.

SUBMITTER: Jiang T

PROVIDER: S-EPMC10265098 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

Jiang Ting T Zhu Jiaojiao J Jiang Shilong S Chen Zonglin Z Xu Ping P Gong Rong R Zhong Changxin C Cheng Yueying Y Sun Xinyuan X Yi Wenjun W Yang Jinming J Zhou Wenhu W Cheng Yan Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230425 17

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction betw ...[more]

PMID: 37096846

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Project description:BackgroundTriple-negative breast cancer (TNBC) is characterized by high malignancy, strong invasiveness, and a propensity for distant metastasis, leading to poor prognosis and relatively limited treatment options. Metformin, as a first-line oral hypoglycemic agent, has garnered widespread research interest in recent years due to its potential in cancer prevention and treatment. However, its efficacy varies significantly across different tumor types. Histone deacetylase inhibitors (HDACi), such as SAHA, have demonstrated antitumor activity, but TNBC responds poorly to HDACi monotherapy, possibly due to feedback activation of the JAK-STAT pathway. Exploring the synergistic potential and underlying mechanisms of combining metformin with HDACi in TNBC treatment is crucial.MethodsWe predicted the synergistic effects of metformin and SAHA in TNBC using multiple computational methods (CMap, DTsyn, and DrugComb). We also developed a cancer-specific compound mimic library (CDTSL) and applied a three-step strategy to identify genes fitting the "metformin sensitization" model. Subsequently, we evaluated the synergistic effects of metformin and SAHA in TNBC cell lines through cell proliferation, colony formation, and apoptosis assays. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as transcriptome sequencing, chromatin immunoprecipitation (ChIP), Western blotting, and measurement of extracellular acidification rate (ECAR). Additionally, we assessed the in vivo antitumor effects of the combined therapy in a nude mouse subcutaneous xenograft model.ResultsCMap, DTsyn, and DrugComb all predicted the synergistic effects of SAHA and metformin in TNBC. The screening results revealed that HDAC10 played a key role in metformin sensitization. We found that the combination of metformin and SAHA exhibited synergistic antitumor effects (combination index CI < 0.9) in TNBC cell lines. Mechanistically, metformin inhibited histone acetylation on FGFR4, thereby blocking the feedback activation of FGFR4 downstream pathways induced by SAHA. Furthermore, metformin interfered with the glycolysis process induced by SAHA, altering the metabolic reprogramming of tumor cells. In in vivo experiments, the combined treatment of metformin and SAHA significantly inhibited the growth of subcutaneous tumors in nude mice.ConclusionsMetformin enhances the sensitivity of TNBC to HDAC inhibitors by blocking the FGFR4 pathway and interfering with metabolic reprogramming. When used in combination with SAHA, metformin exhibits synergistic antitumor effects. Our study provides a theoretical basis for the combined application of HDAC inhibitors and metformin, potentially offering a new strategy for the treatment of TNBC.

Dataset Information

Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

Publications

Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

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