DNA Damage Inducible Transcript 4 Gene: The Switch of the Metabolism as Potential Target in Cancer

Tirado-Hurtado, Indira; Fajardo, Williams; Pinto, Joseph A.

doi:10.3389/fonc.2018.00106

Cited by 98 publications

(87 citation statements)

References 70 publications

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“…DNA damage inducible transcript 4 (DDIT4), also known as REDD1 or RTP801, is induced by various cellular stress conditions, such as hypoxia, endoplasmic reticulum stress, oxidative stress, heat shock and starvation . It inhibits the activity of mammalian target of rapamycin complex 1 (mTORC1), a major player in cell growth, proliferation and survival.…”

Section: Introductionmentioning

confidence: 99%

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Cheng

Dai

Pang

et al. 2019

J Cellular Molecular Medi

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The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event‐free survival (EFS) than the low expressers among the chemotherapy‐only group (all P < .001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo‐HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo‐HSCT had longer EFS and OS than those who received chemotherapy alone (all P < .01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN‐AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo‐HSCT.

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Section: Introductionmentioning

confidence: 99%

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Cheng

Dai

Pang

et al. 2019

J Cellular Molecular Medi

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“…DNA Damage‐Inducible Transcript 4 (DDIT4), also called REgulated in Development and DNA damage response 1 (REDD1), is a highly conserved negative regulator of the mTOR pathway that was first identified as a stress response gene induced upon UV‐ or alkylating agent‐induced DNA damage (Figure ). Not surprisingly, abnormal decreased expression of DDIT4 is associated with multiple diseases, including malignant tumours, whereby mTORC1 becomes hyperactivated . The importance of DDIT4 in cytoprotection and survival has been highlighted in Ddit4 ‐null mice that exhibit enhanced mTOR activity .…”

Section: Vitamin D and Dna Damage Repair Responsementioning

confidence: 99%

“…In addition, DDIT4 is also involved in the suppression of reactive oxygen species, a major driver of oxidative DNA damage. Thus, regulation of DDIT4‐mTOR system by a natural supplement such as vitamin D may be a highly effective way to influence numerous key regulators of the DDR in cancers …”

Section: Vitamin D and Dna Damage Repair Responsementioning

confidence: 99%

“…Not surprisingly, abnormal decreased expression of DDIT4 is associated with multiple diseases, including malignant tumours, whereby mTORC1 becomes hyperactivated. 47,52,53 The importance of DDIT4 in cytoprotection and survival has been highlighted in Ddit4-null mice that exhibit enhanced mTOR activity. 50 Ddit4-null mice are resistant to a diverse set of stress conditions.…”

Section: Integration Of Vitamin D and The Ddr Via The Ddit4-mtor Pamentioning

confidence: 99%

“…a major driver of oxidative DNA damage. Thus, regulation of DDIT4-mTOR system by a natural supplement such as vitamin D may be a highly effective way to influence numerous key regulators of the DDR in cancers 20,47,[49][50][51][53][54][55][56]58,[63][64][65]. …”

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confidence: 99%

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Exploring vitamin D signalling within skin cancer

Vishlaghi

Lisse

2020

Clinical Endocrinology

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Sunlight exposure of the skin is associated with both risks and benefits. On one hand, sunlight ultraviolet (UV) radiation can cause skin cancer through signature DNA mutations. On the other hand, it can be absorbed in the skin by 7‐dehydrocholesterol to instigate endogenous synthesis of vitamin D to regulate anticancer effects. Thus, protecting one's skin from sunlight to avoid skin cancer may lead to impaired vitamin D levels arguing for sensible sun exposure practices. To limit cancer, vitamin D metabolites can promote uncharacterized and diverse sets of events such as repair responses to DNA damage, apoptosis of malignant cells, and suppression of immune surveillance, proliferation and angiogenesis. Recent findings also suggest that part of the anticancer effects of vitamin D within squamous cell carcinoma—a type of skin cancer most directly linked to sun exposure—involves the DDIT4‐mTOR catabolic signalling pathway to enhance cell autophagy. As mTOR activity and cellular metabolism are modulated as part of the DNA damage response, insights into the means by which mTOR can be controlled by vitamin D to suppress cancer is of molecular and clinical importance. Overall, the research so far suggests that presence of vitamin D through sunlight exposure and supplementation are beneficial for human health in the face of cancer.

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

et al. 2023

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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.

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DNA Damage Inducible Transcript 4 Gene: The Switch of the Metabolism as Potential Target in Cancer

Cited by 98 publications

References 70 publications

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Exploring vitamin D signalling within skin cancer

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

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