ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer

Pu, Xiaowen; Gu, Zhuowei; Gu, Zhifeng

doi:10.7150/jca.46097

Cited by 33 publications

(31 citation statements)

References 32 publications

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“…In recent years, ALKBH5 has been increasingly studied in various malignancies and has been found to play dual roles. Previous studies demonstrated that ALKBH5 acted as an oncogene in colon cancer, endometrial cancer, and renal cell carcinoma [27][28][29]. Further, ALKBH5 was found to suppress progression in pancreatic cancer and hepatocellular carcinoma [30,31].…”

Section: Discussionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

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Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

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Section: Discussionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

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“…Liu, et al claims that FTO affects cellular energy metabolism in breast cancer, such as lactic acid, adenosine triphosphate, and hexokinase activity via the PI3K/AKT signaling [38]. As reported by Pu, et al, ALKBH5 expression is obviously elevated in endometrial cancer, and through erasing IGF1R mA-modifications, ALKBH5 positively regulates proliferation and invasion of cancer [39]. With respect to 'readers', both YTHDF1 and YTHDC1 were linked to higher GS, pathological T and pathological N. YTHDF1 is overexpressed in the colorectal cancer (CRC), and inhibition of Wnt/β-catenin pathway can be achieved by YTHDF1 silencing in CRC cells [40].…”

Section: Discussionmentioning

confidence: 92%

Malignant Evaluation and Clinical Prognostic Values of M6A RNA Methylation Regulators in Prostate Cancer

et al. 2021

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Objective: M6A RNA modification is closely associated with tumor genesis and progression of several malignancies; however, its role in prostate cancer (PCa) remains poorly understood. Materials and methods: Expression data and corresponding clinicopathologic information were available freely from the Cancer Genome Atlas (TCGA) dataset. We compared the expression level of m6A RNA methylation regulators in PCa with different clinicopathologic characteristics and identified subgroups based on their expressions with consensus clustering. To build the signature and assess its prognostic value, several methods were used for the analysis, including univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, time-dependent receiver operating curve (ROC), and Kaplan-Meier (KM) survival analysis. Results: Most of the m6A RNA methylation regulators were differentially expressed not only between normal and tumor tissue but also among PCa stratified by different clinicopathologic characteristics. There were obvious differences between two clusters, cluster 1 and 2, regarding clinicopathologic features, and the recurrence-free survival (RFS) in cluster 2 was significantly worse than cluster 1. We developed an eleven-gene signature which exhibited a high prognostic value and was able to independently predict RFS. Moreover, a nomogram which integrated clinical information and the gene signature was capable of distinguishing high-risk recurrent patients. Conclusion:These methylation regulators are correlated to clinicopathologic characteristics in PCa and a prognostic model using m6A methylation-related genes is constructed and of high predictive value for recurrence after RP.

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“…In recent years, ALKBH5 has been increasingly studied in various malignancies and has been found to play dual roles. Previous studies demonstrated that ALKBH5 acted as an oncogene in colon cancer, endometrial cancer, and renal cell carcinoma [29][30][31]. Further, ALKBH5 was found to suppress progression in pancreatic cancer and hepatocellular carcinoma [32,33].…”

Section: Discussionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and platinum resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

Preprint

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Background: Chemotherapy resistance remains a barrier in improving the prognosis of epithelial ovarian cancer (EOC), but its mechanism remains to be elucidated. ALKBH5 has been recently proven to be an RNA N6-methyladenosine (m6A) demethyltransferase associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in platinum-resistant EOC.Methods: Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop.Results: ALKBH5 was upregulated in platinum-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 was found to be the upstream transcription factor of ALKBH5 and formed a loop with ALKBH5., and its overexpression facilitated EOC cell chemoresistance both in vivo and in vitro. HOXA10 overexpression was found to facilitate EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is an m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, and this resulted in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10.Conclusions: The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to platinum. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop maybe a potential strategy to overcome platinum resistance in EOC.

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ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer

Cited by 33 publications

References 32 publications

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Malignant Evaluation and Clinical Prognostic Values of M6A RNA Methylation Regulators in Prostate Cancer

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and platinum resistance in epithelial ovarian cancer

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