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

Jiang, Ting; Zhu, Jiaojiao; Jiang, Shilong; Chen, Zonglin; Xu, Ping; Gong, Renmin; Zhong, Changxin; Cheng, Yueying; Sun, Xinyuan; Yi, Wenjun; Yang, Jin‐Ming; Zhou, Wenhu; Cheng, Yan

doi:10.1002/advs.202207257

Cited by 24 publications

(12 citation statements)

References 47 publications

(68 reference statements)

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“…Next, we investigated how the neddylation signal affected the sensitivity of PTX. We noticed that PTX has been reported as an inducer of autophagy [ 19 ]. Autophagy is a conserved cellular process related to chemoresistance in breast cancer [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Zheng,

Qian,

Wang

et al. 2024

J Exp Clin Cancer Res

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Background Paclitaxel (PTX) treatment resistance is an important factor leading to poor prognosis in triple-negative breast cancer (TNBC), therefore there is an urgent need to identify new target for combination therapy. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Previous studies have found that neddylation is activated in multiple tumors, but its relationship with PTX chemotherapy sensitivity has not been reported. Methods Differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC tissues were validated using public databases and immunohistochemistry. The in vitro and in vivo functional experiments were used to observe the effect of neddylation inhibition combined with PTX therapy on tumor progression. Co-IP, western blot and PCR assays were used to investigate the molecular mechanisms. Molecular docking was used to simulate the protein binding of UBC12 and TRIM25. Molecular dynamics simulation was used to observe the changes in TRIM25 protein conformation. Results We found that in TNBC that is insensitive to PTX, NEDD8 and NEDD8 conjugating enzyme UBC12 are highly expressed. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased the sensitivity of the tumor to PTX, and this increase in sensitivity is related to UBC12-mediated autophagy activation. Mechanistically, UBC12 can transfer NEDD8 to E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) at K117. Molecular dynamics simulations indicate that the neddylation modification of TRIM25 reduces steric hindrance in its RING domain, facilitating the binding of TRIM25 and ubiquitylated substrates. Subsequently, TRIM25 promotes the nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy related genes by increasing K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX. Conclusions Neddylation is activated in PTX-insensitive TNBC. Specifically, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. Neddylation suppression combination with PTX treatment shows a synergistic anti-tumor effect.

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Section: Resultsmentioning

confidence: 99%

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Zheng,

Qian,

Wang

et al. 2024

J Exp Clin Cancer Res

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“…DUSP1 exhibited notable differences in early prognosis, and patients owned poorer prognoses when showing higher expression of DUSP1. In a recent study, Jiang et al 37 demonstrated that lncRNA DDIT4‐AS1 recruits RNA‐binding protein AUF1 to facilitate the interaction between AUF1 and DDIT4 mRNA, thereby stabilizing DDIT4 mRNA and inhibiting the mTORC1 signaling pathway. It induces the regulation of autophagy in TNBC cells and promotes the proliferation, migration, and invasion of TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ferroptosis‐related genes in CD8+ NKT cells and classical monocytes may affect the immunotherapy response after combined treatment in triple negative breast cancer

Liu,

He,

Huang

et al. 2023

Thoracic Cancer

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BackgroundDrug resistance has led to the failure of immunotherapy in triple negative breast cancer patients. Here we aimed to explore the mechanisms of drug resistance in patients in order to enhance their response to immunotherapy.MethodsWe downloaded publicly available single‐cell RNA‐sequencing data of peripheral blood mononuclear cells from patients after treatment to investigate the possible mechanisms of drug resistance. The publicly available TCGA transcriptomic data and somatic mutation data were used for further validation. In this study, a series of bioinformatics and machine learning methods were employed.ResultsWe identified the vital roles of CD8+ NKT cells and classical monocytes in the immunotherapy response of triple‐negative breast cancer patients. The proportion of these cell types was significantly increased in group partial response. We also found that downregulation of ferroptosis‐related genes regulates the immune pathway. The analysis of scRNA data and TCGA transcriptomic data presented that DUSP1 may play a crucial role in immunotherapy resistance.ConclusionOverall, the composition of the tumor microenvironment affects the immunotherapy response of patients, and DUSP1 may be a potential target for overcoming drug resistance.

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“…DNA damage-inducible transcript 4 (DDIT4) is known as a DNA damage derivable transcript, which could be ampli ed in DNA damage [18,19] . Over the past decades, DDIT4 were reported involved in a handful of human cancer, including head and neck carcinoma cancer, osteosarcoma, lung cancer, and breast cancer [20][21][22][23] . Recently, DDIT4 expression was uncovered highly expressed in OC cells and positively connected with patients' poor survival [24] .…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA MCM3AP-AS1 promotes ovarian cancer cells progression by modulating miR-383/DDIT4 axis

Yan,

Chen,

Guo

2023

Preprint

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Long non-coding RNA (lncRNA) was recently reported to be implicated in cancer progression. However, the role of MCM3AP-AS1 in ovarian cancer (OC) remains undetected. In this study, MCM3AP-AS1 expression was elevated in OC tissues. High MCM3AP-AS1 expression was related to advanced tumor stage and poor survival. MCM3AP-AS1 knockdown inhibited OC cells proliferation, migration, invasion and EMT in vitro and suppressed primary tumor growth in vivo. Mechanically, MCM3AP-AS1 sponged miR-383 and upregulated the expression of DDIT4. In addition, the suppression of EMT induced by silencing of MCM3AP-AS1 involved with miR-383 inhibition. In sum, MCM3AP-AS1 promoted cell progression through regulating miR-383/DDIT4, which suggested a novel potential oncogenic target for OC.

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

Cited by 24 publications

References 47 publications

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Regulation of ferroptosis‐related genes in CD8+ NKT cells and classical monocytes may affect the immunotherapy response after combined treatment in triple negative breast cancer

Long noncoding RNA MCM3AP-AS1 promotes ovarian cancer cells progression by modulating miR-383/DDIT4 axis

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