HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

Yan, Zhao; Xing, Chao; Deng, Yihui; Ye, Can; Peng, Hongling

doi:10.1016/j.gendis.2023.02.039

Cited by 24 publications

(17 citation statements)

References 164 publications

(231 reference statements)

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“…HIF1α, a key transcription factor in cellular responses to hypoxia, has been implicated in cancer [ 21 ]. HIF1α is often overexpressed in cancer tissues and associated with patients’ poor clinical prognosis [ 22 – 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…HIF1α is often overexpressed in cancer tissues and associated with patients’ poor clinical prognosis [ 22 – 25 ]. HIF1α promotes tumor progression by regulating the transcription of various genes involved in metabolic reprogramming, metastasis, chemotherapy resistance, and immunosuppression [ 21 ]. HIF1α signaling and its protein stability are tightly controlled by ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

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An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Shi,

Fang,

et al. 2024

Oncogenesis

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Accumulating studies have shown that E3 ligases play crucial roles in regulating cellular biological processes and signaling pathways during carcinogenesis via ubiquitination. Tripartite-motif (TRIM) ubiquitin E3 ligases consist of over 70 members. However, the clinical significance and their contributions to tumorigenesis remain largely unknown. In this study, we analyzed the RNA-sequencing expression of TRIM E3 ligases in colorectal cancer (CRC) and identified 10 differentially expressed genes, among which TRIM1 expression predicted poor prognosis of CRC patients. We demonstrated that TRIM1 expression is positively associated with CRC pathological stages, and higher expression is positively correlated with infiltrating levels of immune cells and immunotherapy biomarkers. TRIM1 expression promotes the proliferation and migration of colorectal cancer cells in vitro and in vivo. Transcriptional analysis showed that TRIM1 is responsible for metabolism promotion and immune suppression. Mechanistically, we found that TRIM1 binds HIF1α and mediates its K63-linked ubiquitination, which is required for HIF1α nuclear translocation and subsequent activation. Ubiquitination occurs at Lys214 in the loop between the two PAS domains of HIF1α, and mutation of Lys214 severely disturbs the function of HIF1α. Besides, HIF1α ubiquitination enhances its binding with proteins involved in cellular trafficking and nucleocytoplasmic transport pathway. Collectively, our results indicate TRIM1’s role in predicting prognosis and reveal how TRIM1 functions to upregulate HIF1α expression and promote tumor cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Shi,

Fang,

et al. 2024

Oncogenesis

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“…Therefore, targeting HIF and its associated pathways is currently being explored for future anticancer therapy. There are several HIF-related mechanisms being studied for future cancer therapies, including HIF inhibitors, anti-angiogenic therapies, combination therapies, hypoxia-activated prodrugs, immunotherapy, biomarkers associated with HIF, gene editing, and RNA interference [52,53].…”

Section: Hif-associated Future Cancer Therapiesmentioning

confidence: 99%

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Musleh Ud Din,

Streit,

Huynh

et al. 2024

IJMS

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In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

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“…Bone is a hypoxic environment, and the hypoxic conditions regulate bone homeostasis [47] . In addition, hypoxia-inducible factors (HIFs) and HIF signaling are associated with tumor growth, angiogenesis and EMT [48] . HIF1α has been shown to be upregulated in a hypoxic primary breast cancer microenvironment [49] .…”

Section: Osteoblasts Regulating Cancer Cell Colonization and Growthmentioning

confidence: 99%

The osteoblast in regulation of tumor cell dormancy and bone metastasis

Zarrer,

Taipaleenmäki

2024

Journal of Bone Oncology

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HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

Cited by 24 publications

References 164 publications

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

The osteoblast in regulation of tumor cell dormancy and bone metastasis

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