DDIT4 promotes malignancy of head and neck squamous cell carcinoma

Abstract

This study investigated the cancer-promoting effect of ferroptosis regulator DNA damage-inducible transcript 4 (DDIT4) and its relevant mechanisms. Vital ferroptosis-related genes were identified using bioinformatic methods on the basis of data collected from TCGA and seven other online databases. Cell Counting Kit-8 (CCK8), colony formation, wound-healing and transwell assays, and western blot analysis were conducted for verifying the biological role of DDIT4 in vitro. The immune score and tumor purity were calculated using R package "estimate." The relationship was identified between DDIT4 expression and immune cell infiltration using ssGSEA and CIBERSORT algorithms. R package "Seurat" was used to perform unsupervised clustering of the single cells, and "SingleR" was utilized for annotation. R package "STUtility" was employed to plot the spatial expression of DDIT4. For trajectory analysis, monocle was used to predict cell differentiation and demonstrate the expression of DDIT4 at each state. Here, DDIT4 overexpression was observed in Head and Neck Squamous Cell Carcinoma (HNSCC) cohort, and DDIT4 upregulation showed a positive correlation with larger tumor size, lymph node metastasis, more advanced TNM stage and higher tumor mutational burden (TMB). Moreover, DDIT4 knockdown could markedly inhibit the proliferation, colony formation, invasion and migration of HNSCC cells, as well as suppress the expression of HIF-1a, VEGF and vimentin. In comparison, DDIT4 overexpression showed a negative correlation with immune score and infiltrations of several immune cells. DDIT4 played crucial roles in the differentiation of CAFs and T cells. Collectively, this study demonstrates that DDIT4 contributes a critical role in HNSCC progression. The positive feedback regulation between DDIT4 and HIF-1a may be a potential target for HNSCC treatment.

Comparative analysis of single-cell transcriptome reveals heterogeneity in the tumor microenvironment of lung adenocarcinoma and brain metastases

“…DDIT4, also known as DNA damage response1 and stress-triggered protein, is mainly found in the cytoplasm and nucleus [ 21 ]. Compared with normal tissues, high expression of DDIT4 was observed in a variety of tumor tissues, such as colorectal cancer, glioma, head and neck squamous cell carcinoma, and gastric cancer [ 45 – 48 ]. Moreover, upregulation of DDIT4 expression contributes to the reduction of apoptotic processes and promotes proliferation, migration, and invasion of tumor cells in in vitro and in vivo tumor studies.…”

NET-related gene signature for predicting AML prognosis

“…DNA damage inducible transcript 4 (DDIT4), an inhibitor of the mammalian target of rapamycin (mTOR), is expressed in response to various cellular stresses 41 . Research indicates that in various malignancies, DDIT4 is involved in tumorigenesis and influences patient survival 42 – 44 . Studies have confirmed that high DDIT4 expression may be a poor prognostic indicator for AML 45 .…”

Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway

“…However, the alterations in DDIT4 expression and function are dependent on cancer type, since DDIT4 may play either oncogenic or tumor suppressor role in different types of cancer [27]. For example, DDIT4 overexpression was observed in lung adenocarcinoma and head and neck squamous cell carcinoma, with its upregulation showing a positive correlation with poor prognosis [28,29]. In contrast, downregulation of DDIT4 was associated with tumor cell proliferation in HER2-positive and triple-negative breast cancer [30].…”