HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer

Zhou, Qingqing; Liu, Tengfei; Qian, Wenjing; Ji, Jun; Cai, Qu; Jin, Yangbing; Jiang, Jinling; Zhang, Jun

doi:10.1038/s41419-023-05868-z

Cited by 17 publications

(6 citation statements)

References 62 publications

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“…Prior research has unveiled the intricate involvement of ferroptosis in GC, linking it to cell proliferation, metastasis, and chemotherapy resistance. Key genes and non‐coding RNAs, such as BAP31, [ 30 ] GPX4, [ 31 ] STAT3, [ 32 ] ATF2, [ 33 ] and ARF6, [ 34 ] play pivotal roles in orchestrating ferroptosis in GC, shedding light on its significant contribution to GC development and providing novel avenues for therapeutic exploration.…”

Section: Discussionmentioning

confidence: 99%

Blocking Ubiquitin‐Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl‐CoA Desaturase

Guan,

Wang,

et al. 2024

Advanced Science

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Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin‐specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo‐resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti‐tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl‐CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation.

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Section: Discussionmentioning

confidence: 99%

Blocking Ubiquitin‐Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl‐CoA Desaturase

Guan,

Wang,

et al. 2024

Advanced Science

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“…ASCL1 can promote progression of castration-resistant prostate cancer to neurosecretory prostate cancer by mediating ferroptosis resistance [ 58 ]. In gastric cancer cells, the HNF4A-BAP31-VDAC1 axis synchronously regulates tumor cell proliferation and ferroptosis [ 59 ]. The occurrence of ferroptosis is regulated by several genes, such as GPX4, CDKN1A, SLC1A5, and ACSL4, etc.…”

Section: Discussionmentioning

confidence: 99%

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer

Li,

Peng,

Wang

2023

Aging

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Colorectal cancer is one of the most common malignant tumors in the digestive system, and its high incidence and metastasis rate make it a terrible killer that threatens human health. In-depth exploration of the targets affecting the progression of colorectal cancer cells and the development of specific targeted drugs for them are of great significance for the prognosis of colorectal cancer patients. Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph subfamily with tyrosine kinase activity, plays a key role in the regulation of signaling pathways related to the malignant phenotype of various tumor cells, but its specific regulatory mechanism in colorectal cancer needs to be further clarified. Here, we found that EphA2 was abnormally highly expressed in colorectal cancer and that patients with colorectal cancer with high EphA2 expression had a worse prognosis. We also found that EphA2 can form liquid-liquid phase separation condensates on cell membrane, which can be disrupted by ALW-II-41-27, an inhibitor of EphA2. In addition, we found that EphA2 expression in colorectal cancer was positively correlated with the expression of ferroptosis-related genes and the infiltration of multiple immune cells. These findings suggest that EphA2 is a novel membrane protein with phase separation ability and is associated with ferroptosis and immune cell infiltration, which further suggests that malignant progression of colorectal cancer may be inhibited by suppressing the phase separation ability of EphA2.

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“…This suggests that DCLK3 has the potential to be a valuable prognostic marker in GC patients 120 . It has been reported that B‐cell receptor‐associated protein 31 (BAP31), through its interaction with Voltage‐Dependent Anion Channel 1 (VDAC1), regulates ferroptosis 121 . Furthermore, FSP1, CDGSH iron sulfur domain 1 (CISD1), and microsomal glutathione S‐transferase 1 (MGST1) have been identified as key suppressors of ferroptosis in GC 122 .…”

Section: Ferroptosis In Gcmentioning

confidence: 99%

“…120 It has been reported that Bcell receptor-associated protein 31 (BAP31), through its interaction with Voltage-Dependent Anion Channel 1 (VDAC1), regulates ferroptosis. 121 Furthermore, FSP1, CDGSH iron sulfur domain 1 (CISD1), and microsomal glutathione S-transferase 1 (MGST1) have been identified as key suppressors of ferroptosis in GC. 122 MGST1, in particular, exhibits notable upregulation in GC and promotes the progression of GC while inhibiting ferroptosis, indicating its potential as a standalone prognostic factor.…”

Section: Prognostic and Diagnostic Markers Associated With Ferroptosi...mentioning

confidence: 99%

Targeting ferroptosis in gastric cancer: Strategies and opportunities

Le,

Pan,

Zhang

et al. 2023

Immunological Reviews

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SummaryFerroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron‐dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.

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HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer

Cited by 17 publications

References 62 publications

Blocking Ubiquitin‐Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl‐CoA Desaturase

Blocking Ubiquitin‐Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl‐CoA Desaturase

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer

Targeting ferroptosis in gastric cancer: Strategies and opportunities

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