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

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

  • Adv Sci (Weinh). 2023 Apr 25;e2207257. doi: 10.1002/advs.202207257.
Ting Jiang 1 2 3,  Jiaojiao Zhu 2,  Shilong Jiang 4,  Zonglin Chen 1,  Ping Xu 1,  Rong Gong 1,  Changxin Zhong 1,  Yueying Cheng 1,  Xinyuan Sun 1 2 3,  Wenjun Yi 5,  Jinming Yang 6,  Wenhu Zhou 2,  Yan Cheng 1 3 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China.
  • 3 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China.
  • 4 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 5 Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 6 Department of Cancer Biology and Toxicology, Department of Pharmacology, College of Medicine and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
  • 7 Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, 410011, China.
PMID: 37096846 DOI: 10.1002/advs.202207257
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.

Keywords

TNBC; autophagy; chemotherapy; lncRNA DDIT4-AS1; nanoparticle.

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