HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5

Huo, Fu‐Chun; Zhu, Zhansheng; Du, Wen‐Qi; Pan, Yao‐Jie; Jiang, Xin; Kang, Meng-jie; Liu, Bowen; Mou, Jie; Pei, Dong‐Sheng

doi:10.1016/j.phrs.2023.106863

Cited by 12 publications

(4 citation statements)

References 45 publications

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“… 20 In addition, some studies have reported that the expression of FTO and ALKBH5 is significantly up-regulated in cervical cancer and significantly enhances the malignant phenotype of cervical cancer cells. 21–23 The pro-cancer mechanism of FTO and ALKBH5 may also include the removal of m6A modification of DIRAS1 mRNA, which reduces the DIRAS1 protein levels.…”

Section: Discussionmentioning

confidence: 99%

M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells

Wang,

Ye,

Zhao

et al. 2024

Cancer Biology & Therapy

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DIRAS family GTPase 1 (DIRAS1) has been reported as a potential tumor suppressor in other human cancer. However, its expression pattern and role in cervical cancer remain unknown. Knockdown of DIRAS1 significantly promoted the proliferation, growth, migration, and invasion of C33A and SiHa cells cultured in vitro . Overexpression of DIRAS1 significantly inhibited the viability and motility of C33A and SiHa cells. Compared with normal cervical tissues, DIRAS1 mRNA levels were significantly lower in cervical cancer tissues. DIRAS1 protein expression was also significantly reduced in cervical cancer tissues compared with para-cancerous tissues. In addition, DIRAS1 expression level in tumor tissues was significantly negatively correlated with the pathological grades of cervical cancer patients. DNA methylation inhibitor (5-Azacytidine) and histone deacetylation inhibitor (SAHA) resulted in a significant increase in DIRAS1 mRNA levels in C33A and SiHa cells, but did not affect DIRAS1 protein levels. FTO inhibitor (FB23–2) significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels. Moreover, the down-regulation of METTL3 and METTL14 expression significantly inhibited DIRAS1 protein expression, whereas the down-regulation of FTO and ALKBH5 expression significantly increased DIRAS1 protein expression. In conclusion, DIRAS1 exerts a significant anti-oncogenic function and its expression is significantly downregulated in cervical cancer cells. The m6A modification may be a key mechanism to regulate DIRAS1 mRNA stability and protein translation efficiency in cervical cancer.

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Section: Discussionmentioning

confidence: 99%

M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells

Wang,

Ye,

Zhao

et al. 2024

Cancer Biology & Therapy

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“…A total of nine humans and thirteen Arabidopsis thaliana ALKBH proteins have been identified, which exhibit a range of diverse functions [ 19 ]. Recent studies have demonstrated that ALKBH1 [ 20 ], ALKBH5 [ 21 – 24 ], ALKBH8 [ 19 ], and FTO [ 25 , 26 ] function as tRNA demethylases, which are associated with a range of diseases, including obesity, osteoporosis, diabetes and multiple cancers [ 27 , 28 ]. In humans, FTO regulates adipogenesis through tyrosine protein kinase, Cyclin-A2, and cyclin-dependent kinase 2, demonstrating an interaction between FTO and obesity at multiple levels of human metabolism [ 19 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer

Jiang,

Zhu,

Ding

et al. 2024

Cell Death Dis

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Abstract5-Fluorouracil (5-FU) is the primary treatment option for advanced gastric cancer. However, the current challenge lies in the absence of validated biomarkers to accurately predict the efficacy and sensitivity of 5-FU in individual patients. It has been confirmed that 5-FU can regulate tumor progression by promoting gasdermin E (GSDME, encoded by DFNA5) cleavage to induce pyroptosis. Lysine demethylase ALKBH4 has been shown to be upregulated in a variety of tumors to promote tumor progression. However, its role in gastric cancer is not clear. In this study, we observed a significant upregulation of ALKBH4 expression in gastric cancer tissues compared to adjacent normal tissues, indicating its potential as a predictor for the poor prognosis of gastric cancer patients. On the contrary, GSDME exhibits low expression levels in gastric cancer and demonstrates a negative correlation with poor prognosis among patients diagnosed with gastric cancer. In addition, we also found that high expression of ALKBH4 can inhibit pyroptosis and promote the proliferation of gastric cancer cells. Mechanistically, ALKBH4 inhibits GSDME activation at the transcriptional level by inhibiting H3K4me3 histone modification in the GSDME promoter region, thereby reducing the sensitivity of gastric cancer cells to 5-FU treatment. These findings provide further insight into the regulatory mechanisms of ALKBH4 in the progression of gastric cancer and underscore its potential as a prognostic marker for predicting the sensitivity of gastric cancer cells to 5-FU treatment.

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“…16 Other studies have reported that HPV oncogenic proteins advance aerobic glycolytic capacity or autophagy inhibition to promote cervical cancer progression through m6A methylation modification. [17][18][19] However, the detailed mechanism by which HPV infection participates in the progression of CSCC through m6A methylation modification remains largely unknown and is worth further exploration.…”

mentioning

confidence: 99%

“…Targeting this signalling axis might be a potential strategy for the prevention and treatment of CSCC. in CSCC samples was determined by using a polymerase chain reaction (PCR)-reverse dot blot assay kit (LBP, Guangzhou, China) according to the manufacturer's protocol, which covered the detection of 28 HPV subtypes, including HPV types 16,18,26,31,33,35,39,45,51,52,53,56,58,59,66,68,73,82,6,11,40,42,43,44,54,61, 81 and 83.…”

mentioning

confidence: 99%

N6‐methyladenosine methylation on FSCN1 mediated by METTL14/IGF2BP3 contributes to human papillomavirus type 16‐infected cervical squamous cell carcinoma

Tian,

Huang,

Zhang

et al. 2024

Clin Exp Pharma Physio

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Human papillomavirus (HPV) infection has been reported to be associated with N6‐methyladenosine (m6A) modification in cancers. However, the underlying mechanism by which m6A methylation participates in HPV‐related cervical squamous cell carcinoma (CSCC) remains largely unclear. In this study, we observed that m6A regulators methyltransferase like protein (METTL14) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) were upregulated in HPV‐positive CSCC tissues and cell lines, and their high expression predicted poor prognosis for HPV‐infected CSCC patients. Cellular functional experiments verified that HPV16 oncogenes E6/E7 upregulated the expression of METTL14 and IGF2BP3 to promote cell proliferation and epithelial mesenchymal transition of CSCC cells. Next, we found that E6/E7 stabilized fascin actin‐bundling protein 1 (FSCN1) mRNA and elevated FSCN1 expression in CSCC cells through upregulating METTL14/IGF2BP3‐mediated m6A modification, and FSCN1 expression was also validated to be positively associated with worse outcomes of HPV‐positive CSCC patients. Finally, HPV16‐positive CSCC cell lines SiHa and CaSki were transfected with knockdown vector for E6/E7 or METTL14/IGF2BP3 and overexpressing vector for FSCN1, and functional verification experiments were performed through using MTT assay, flow cytometry, wound healing assay and tumour formation assay. Results indicated that knockdown of E6/E7 or METTL14/IGF2BP3 suppressed cell proliferation, migration and tumorigenesis, and accelerated cell apoptosis of HPV‐positive CSCC cells. Their tumour‐suppressive effects were abolished through overexpressing FSCN1. Overall, HPV E6/E7 advanced CSCC development through upregulating METTL14/IGF2BP3‐mediated FSCN1 m6A modification.

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HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5

Cited by 12 publications

References 45 publications

M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells

M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells

ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer

N6‐methyladenosine methylation on FSCN1 mediated by METTL14/IGF2BP3 contributes to human papillomavirus type 16‐infected cervical squamous cell carcinoma

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