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ALKBH4 functions as a hypoxia-responsive tumor suppressor and inhibits metastasis and tumorigenesis

Year: 2024
Type: article
Abstract: PURPOSE: The human AlkB homolog (ALKBH) dioxygenase superfamily plays a crucial role in gene regulation and is implicated in cancer progression. Under hypoxic conditions, hypoxia-inducible factors (HIFs) dynamically regulate methylation by controlling various dioxygenases, thereby modulating gene expression. However, the role of hypoxia-responsive AlkB dioxygenase remains unclear. METHODS: The molecular events were examined using real-time PCR and Western blot analysis. Tumor cell aggressiveness was evaluated through migration, invasion, MTT, trypan blue exclusion, and colony formation assays. In vivo metastatic models and xenograft experiments were conducted to evaluate tumor progression. RESULTS: Here, we examined the expression of the ALKBH superfamily under hypoxic conditions and found that ALKBH4 expression was negatively regulated by hypoxia. Knockdown of ALKBH4 enhanced the epithelial-mesenchymal transition (EMT), cell migration, invasion, and growth in vitro. The silencing of ALKBH4 enhanced metastatic ability and tumor growth in vivo. Conversely, overexpression of ALLKBH4 reversed these observations. Furthermore, overexpression of ALKBH4 significantly reversed hypoxia/HIF-1α-induced EMT, cell migration, invasion, tumor metastasis, and tumorigenicity. Notably, high expression of ALKBH4 was associated with better outcomes in head and neck cancer and breast cancer patients. Enrichment analysis also revealed that ALKBH4 was negatively enriched in hypoxia-related pathways. Clinically, a negative correlation between ALKBH4 and HIF-1α protein expression has been observed in tissues from both head and neck cancers and breast cancers. CONCLUSION: These findings collectively suggest that ALKBH4 acts as a tumor suppressor and holds therapeutic potential for hypoxic tumors.
DOI: 10.1007/s13402-024-01004-x
Authors: Ji-Lin Chen, Pei-Hua Peng, Han-Tsang Wu, Dar-Ren Chen, Ching-Yun Hsieh, Jeng-Shou Chang, Joseph Lin, Huan-Yu Lin, Kai-Wen Hsu
Institutions: Taipei Veterans General Hospital, China Medical University, Chang Gung Memorial Hospital, Taoyuan Chang Gung Memorial Hospital, Linkou Chang Gung Memorial Hospital, Changhua Christian Hospital, Chung Shan Medical University, China Medical University Hospital, Cheng Ching Hospital
Language: English
Subfield: Cancer Research
Open Access status: gold
Estimated APC paid: $4,390
Funders: National Science and Technology Council, Chang Gung Medical Foundation, Ministry of Science and Technology, Taiwan, Chang Gung Memorial Hospital, Linkou, China Medical University, China Medical University, Taiwan, National Science and Technology Council
Awards: G125277381, G2205640134, The Role and Mechanism of Long Non-Coding Rna Rp11-367g18.1-V2 in Promoting Progression of Clear Cell Renal Cell Carcinoma, The Role and Regulatory Mechanism of 2′-O-Methyladenosine (Am) Modification of Lncrna Mahac in Hypoxia-Induced Tumor Progression( II ), The Role and Molecular Mechanism of Mettl25-Mediated Rna 2′-O-Methyladenosine (Am) Modification in Epigenetic Regulation and Hypoxia-Induced Tumor Progression, The Role and Regulatory Mechanism of 2′-O-Methyladenosine (Am) Modification of Lncrna Mahac in Hypoxia-Induced Tumor Progression( III ), G7241640770, G7489393043, The Mechanism and Application of Usp7 and Usp7-Induced Long-Non Coding Rna in the Chemoresistance of Triple-Negative Breast Cancer, G951433114
OpenAlex ID: W4403405983
FWCI: 0.61
Cites: 39
Cited by: 4
Related to: 10