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PubMed2026

Enhancer-mediated DDIT4 activation by SMYD2-dependent H3K4me1 promotes pazopanib resistance in clear cell renal cell carcinoma.

BACKGROUND: The progression and resistance to targeted therapy, including pazopanib, frequently lead to poor prognosis in clear cell renal cell carcinoma (ccRCC) patients. However, the underlying molecular mechanisms of these processes remain unclear. METHODS: In this study, we first performed RNA-seq to identify genes that were differentially expressed in both SMYD2-knockdown and pazopanib-resistant cells, indicating their potential role in SMYD2-mediated drug resistance. We analyzed TCGA-KIRC data and 150 patient samples to identify the relationship between SMYD2 and DDIT4 expression levels, as well as the prognostic significance of DDIT4. In vitro functional assays and murine models were applied to evaluate the effects of SMYD2 and DDIT4 on tumor growth and on pazopanib resistance. CUT&Tag and chromosome conformation capture (4 C) assays were applied to identify enhancers associated with SMYD2-mediated regulation of DDIT4, while the JASPAR database was utilized to predict transcription factors involved in the enhancer regulation. CRISPR-mediated enhancer deletion and ChIP-qPCR were subsequently performed to validate the regulatory roles of the identified enhancer and the transcription factor SPI1 in DDIT4 expression. RESULTS: Our study revealed that the expression level of DDIT4 is positively correlated with SMYD2. DDIT4 is highly expressed in renal cell carcinoma and is associated with poorer survival outcomes. Further research revealed that SMYD2 regulates H3K4me1 in a DDIT4 distal enhancer (chr10:72830412-72830891), promoting the recruitment of the transcription factor SPI1, thereby activating DDIT4 expression. We found that DDIT4 promotes the proliferation, metastasis, and pazopanib resistance of ccRCC, and DDIT4 knockdown enhances drug sensitivity in both in vitro and in vivo experiments. Furthermore, the SMYD2-DDIT4 axis activates the downstream STAT3 signaling pathway, thereby promoting tumor progression. In addition, DDIT4-related prognostic features showed potential associations with patient survival and predicted drug sensitivity in computational analyses. CONCLUSIONS: Our study identifies a previously unrecognized SMYD2-enhancer-DDIT4 regulatory axis, which promotes tumor progression and pazopanib resistance in ccRCC. These findings may provide potential therapeutic implications to overcome pazopanib resistance and improve treatment outcomes in ccRCC by targeting the SMYD2-enhancer-DDIT4 axis.

Carcinoma, Renal Cell↗

PubMed2024

The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis.

BACKGROUND & AIMS: Helicobacter pylori (H pylori) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of H pylori infection. METHODS: Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on Ddit4+/+ and Ddit4-/- mice infected with H pylori strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe2+, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins. RESULTS: DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to H pylori infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post H pylori infection. Notably, H pylori infection led to more severe gastric metaplasia lesion in Ddit4-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected Ddit4-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted H pylori-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted H pylori-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis. CONCLUSIONS: Our results indicate that DDIT4 serves as a protective factor against H pylori-induced gastric metaplasia by metabolic resistance to ferroptosis.

Ferroptosis↗

PubMed2025

Establishment of a prognostic model based on ER stress-related cell death genes and proposing a novel combination therapy in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy, presenting significant challenges in accurately predicting patient prognosis. Dysregulation of endoplasmic reticulum (ER) stress and resistance to programmed cell death (PCD) are hallmarks of AML cells. However, the prognostic significance of the interplay between ER stress and cell death pathways in AML remains largely unexplored. METHODS: We analyzed RNA sequencing and clinical data from 887 AML patients across 4 cohorts to develop an ER stress-related cell death index (ERCDI) using 10 machine-learning algorithms with 117 unique combinations. Survival and time-dependent Receiver Operating Characteristic Curve (ROC) analyses were performed to assess the model's efficacy. Clinical characteristics, the tumor immune microenvironment, and drug sensitivity differences between the high- and low-risk groups were also analyzed. The CMap database was used to identify potential therapeutic drugs. In vitro and in vivo experiments, including CCK-8, colony formation, flow cytometry, Transwell assays, and xenograft mouse models, were conducted to evaluate the effects of the target genes and candidate drugs. RESULTS: The ERCDI demonstrated strong prognostic and predictive performance for prognosis in AML patients. Furthermore, the ERCDI effectively predicted immunotherapy and chemotherapy outcomes and was associated with the immune features of the different risk groups. DNA damage-inducible transcript 4 protein (DDIT4), a key gene associated with ERCDI, is related to poor prognosis in AML patients with high expression. Additionally, the knockdown of DDIT4 significantly inhibited AML cell proliferation, induced cell apoptosis, and promoted cell cycle arrest. Chaetocin was subsequently identified as a candidate compound for AML treatment. Subsequent experiments suggested that combining chaetocin and venetoclax is a potentially promising therapeutic strategy for AML. CONCLUSION: The ERCDI provides personalized risk assessment and treatment recommendations for individual AML patients. The combined use of chaetocin and venetoclax can potentially be repurposed for AML therapy.

Humans↗

PubMed2026

A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.

Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, limiting efforts to exploit these enzymes for targeted protein degradation. Here we combine genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution, both coupled to an endogenous knock-in reporter of the SCLC lineage oncogenic transcription factor ASCL1, to systematically interrogate the mechanisms governing its degradation. These complementary screens unbiasedly identify the HECT ubiquitin ligase HUWE1 as the dominant regulator of ASCL1 stability in small cell lung cancer (SCLC) and resolve a conserved C-terminal phospho-degron centered on Ser207 and terminal Trp/Phe residues that are required for HUWE1 docking and ubiquitin-mediated degradation. Unexpectedly, base editor screening further uncovers a previously unrecognized regulatory module within HUWE1: a short negatively charged helix that functions as an autoinhibitory gate controlling access of phospho-degron substrates to HUWE1. Charge-flipping mutations within this regulatory helix relieve autoinhibition and accelerate degradation of multiple HUWE1 phospho-degron substrates, including ASCL1 and the canonical HUWE1 substrate DDIT4. Stabilization of ASCL1 through degron disruption paradoxically impairs SCLC proliferation, revealing that dynamic proteasome-coupled turnover is required for transcription factor function. Together, these findings reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement. They also illustrate a generalizable strategy for resolving degradation mechanisms of undruggable transcription factors in their endogenous cellular context.

ASCL1↗