High expression of AlkB homolog 5 suppresses the progression of non-small cell lung cancer by facilitating ferroptosis through m6A demethylation of SLC7A11.

Non-small cell lung cancer (NSCLC) is a prevailing LC characterized by poor outcomes. AlkB homolog 5 (ALKBH5) functions as a tumor suppressor in several cancers. This study delved into the role of ALKBH5 in NSCLC development. TCGA database predicted ALKBH5 expression in NSCLC patients. ALKBH5 levels in NSCLC and human bronchial epithelial cells were determined. pcDNA3.1-ALKBH5/NC, pcDNA3.1-SLC7A11/NC, and ferrostatin-1 were used to explore the interactions among ALKBH5, SLC7A11, and ferroptosis. SLC7A11 mRNA and its protein levels were measured by RT-qPCR and Western blot. Cell viability, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and Transwell. Total N6-methyladenosine (m6A) quantification and its enrichment on SLC7A11 mRNA were determined, followed by the observation of Ki67, ALKBH5 and SLC7A11-positive cell numbers. Glutathione (GSH), lipid reactive oxygen species (lipid-ROS), malondialdehyde (MDA), and iron ion contents were determined. Animal experiments further analyzed the role of ALKBH5 in tumor development and glutathione peroxidase 4 (GPX4) expression. Bioinformatics analysis revealed the lowly-expressed ALKBH5 in LC patients. ALKBH5 was downregulated in NSCLC cells and its upregulation repressed proliferation activity, invasion, and migration, and facilitated apoptosis. ALKBH5 upregulation decreased GSH, increased lipid-ROS, MDA, and iron ion contents, and downregulated SLC7A11 by reducing m6A modification. SLC7A11 upregulation partly annulled the effect of ALKBH5 overexpression on cell ferroptosis and malignant behaviors. In vivo assays elucidated the suppression of ALKBH5 upregulation on tumor development and GPX4 levels. ALKBH5 upregulation downregulates SLC7A11 transcription by decreasing m6A modification, thus promoting NSCLC cell ferroptosis and ultimately repressing NSCLC progression.

Huang Z ，Lin G ，Hong Y ，Weng L ，Zhu K ，Zhuang W ... -  《-》

ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells.

Colorectal cancer (CRC) is the major subtype of gastrointestinal malignancy and involves cancer-related genes and signaling pathways to regulate ferroptosis. The present study was conducted to analyze the role of alkB homolog 5 (ALKBH5) in the ferroptosis of CRC cells and provide novel targets for CRC treatment. The transcriptional and protein levels of ALKBH5 and solute carrier family 7 members 11 (SLC7A11) in tissues and cells were determined by qRT-PCR and Western blot assay. HCT116 and SW620 cells were transfected with ALKBH5 overexpression vectors to determine cell viability and levels of reactive oxygen species (ROS), Fe+, glutathione, and glutathione peroxidase 4 using cell counting kit-8, colony formation, fluorescence probe, assay kits, and Western blot assay. The N6-methyladenosine (m6A) level and the enrichment of m6A on SLC7A11 mRNA were measured by m6A quantitative analysis and m6A methylated RNA immunoprecipitation-qPCR, and the mRNA stability was determined after actinomycin D treatment. CRC cells were treated with the combination of SLC7A11 and ALKBH5 overexpression vectors to confirm the mechanism. Nude mice were subcutaneously injected with CRC cells overexpressing ALKBH5. ALKBH5 was downregulated in CRC and ALKBH5 overexpression promoted ROS release and ferroptosis. ALKBH5 erased the m6A modification on SLC7A11 mRNA to reduce the mRNA stability of SLC7A11, further reducing SLC7A11 expression. SLC7A11 overexpression reversed the promotive role of ALKBH5 overexpression in ferroptosis. ALKBH5 upregulation mitigated tumor growth in vivo. ALKBH5 reduced SLC7A11 transcription by erasing m6A modification, thus promoting the ferroptosis of CRC cells.

Luo J ，Yu H ，Yuan Z ，Ye T ，Hu B ... -  《-》

ALKBH5 Modulates Asthma Progression by Downregulating N6-methyladenosine Methylation.

Fan X ，Wei C ，Han Y 《-》

N(6)-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability.

Mounting evidence demonstrates that N6-methyladenosine (m6A) play critical roles of m6A in the epigenetic regulation, especially for human cancer. The m6A modification is installed by methyltransferase and erased demethylases, leading to the significant modification for gene expression and cell fate. Here, we investigated the biological roles and mechanism of demethylase alkylation repair homolog protein 5 (ALKBH5) in the non-small cell lung cancer (NSCLC). Results revealed that ALKBH5 was ectopically up-regulated in the NSCLC tissue and cells, and closely correlated with the poor prognosis. Functionally, ALKBH5 promoted the proliferation and reduced apoptosis of NSCLC cells in vitro, and knockdown of ALKBH5 repressed the tumor growth in vivo. Mechanistically, RNA immunoprecipitation sequencing (RIP-Seq) revealed that ALKBH5 targeted the TIMP3. Moreover, ALKBH5 repressed TIMP3 mRNA stability and protein production. In conclusion, the present research confirmed the ALKBH5/TIMP3 pathway in the NSCLC oncogenesis progress, providing a novel insight for the epitranscriptome and potential therapeutic target for NSCLC.

Zhu Z ，Qian Q ，Zhao X ，Ma L ，Chen P ... -  《-》

m(6)A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC.

Jin D ，Guo J ，Wu Y ，Yang L ，Wang X ，Du J ，Dai J ，Chen W ，Gong K ，Miao S ，Li X ，Sun H ... -  《Molecular Cancer》