RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer
Abstract Background Energy balance has long been known to extend lifespans and inhibit carcinogenesis in multiple species by slowing age‐related epigenetic changes while the underlying mechanisms remain largely unknown. Herein, we found that starvation activated autophagy to remodel the DNA methylat...
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1337 |
| _version_ | 1797771155197657088 |
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| author | Liyuan Zhu Yiran Zhu Fang Li Yuan Meng Hanying Wang Wenxia Xu Jingfeng Luo Xian Wang Lifeng Feng Hongchuan Jin |
| author_facet | Liyuan Zhu Yiran Zhu Fang Li Yuan Meng Hanying Wang Wenxia Xu Jingfeng Luo Xian Wang Lifeng Feng Hongchuan Jin |
| author_sort | Liyuan Zhu |
| collection | DOAJ |
| description | Abstract Background Energy balance has long been known to extend lifespans and inhibit carcinogenesis in multiple species by slowing age‐related epigenetic changes while the underlying mechanisms remain largely unknown. Herein, we found that starvation activated autophagy to remodel the DNA methylation profile by inhibiting DNMT3a expression. Methods Illumina Infinium MethylationEPIC BeadChip and dot blot assay were performed to quantify the global DNA methylation level. Protein−RNA interactions were validated through RNA immunoprecipitation and RNA pull‐down assay. In vitro and in vivo experiments were carried out to testify the effect of DNMT3a on chemoresistance. Results Autophagy is impaired in chemoresistance which was associated with differential DNA methylation and could be reversed by DNMT3a inhibition. Autophagy activation decreases the expression of DNMT3a mRNA, accompanied with the downregulation of chemoresistance‐related Linc00942. Knockdown of Linc00942 reduces DNMT3a expression and genome‐wide DNA methylation while Linc00942 overexpression increased DNMT3a expression and correlated hypermethylation in cancer cells and primary tumour tissues. Mechanistically, Linc00942 recruits RNA methyltransferase METTL3 to stimulate N6‐methyladenosine (m6A) deposit on DNMT3a transcripts, triggering IGF2BP3/HuR to recognize modified mRNA for reinforced stability. SQSTM1/p62 recruits Linc00942 for autophagic degradation which can be abrogated after autophagy inhibition by p62 knockdown or chloroquine treatment. Conclusions Inhibition of autophagy increases Linc00942 expression to promote chemoresistance and autophagy activation or hypomethylating agent decitabine restores chemosensitivity by reducing global DNA methylation. Overall, this study identifies a novel methylation cascade linking impaired RNautophagy to global hypermethylation in chemoresistance, and provides a rationale for repurposing decitabine to overcome chemoresistance in cancer treatment. |
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| language | English |
| last_indexed | 2024-03-12T21:33:27Z |
| publishDate | 2023-07-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-51bcfa03bc8347cc834773a5dc064a2d2023-07-27T15:20:29ZengWileyClinical and Translational Medicine2001-13262023-07-01137n/an/a10.1002/ctm2.1337RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancerLiyuan Zhu0Yiran Zhu1Fang Li2Yuan Meng3Hanying Wang4Wenxia Xu5Jingfeng Luo6Xian Wang7Lifeng Feng8Hongchuan Jin9Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaDepartment of Medical Oncology Sir Run Run Shaw Hospital School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaDepartment of Medical Oncology Sir Run Run Shaw Hospital School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University HangzhouChinaAbstract Background Energy balance has long been known to extend lifespans and inhibit carcinogenesis in multiple species by slowing age‐related epigenetic changes while the underlying mechanisms remain largely unknown. Herein, we found that starvation activated autophagy to remodel the DNA methylation profile by inhibiting DNMT3a expression. Methods Illumina Infinium MethylationEPIC BeadChip and dot blot assay were performed to quantify the global DNA methylation level. Protein−RNA interactions were validated through RNA immunoprecipitation and RNA pull‐down assay. In vitro and in vivo experiments were carried out to testify the effect of DNMT3a on chemoresistance. Results Autophagy is impaired in chemoresistance which was associated with differential DNA methylation and could be reversed by DNMT3a inhibition. Autophagy activation decreases the expression of DNMT3a mRNA, accompanied with the downregulation of chemoresistance‐related Linc00942. Knockdown of Linc00942 reduces DNMT3a expression and genome‐wide DNA methylation while Linc00942 overexpression increased DNMT3a expression and correlated hypermethylation in cancer cells and primary tumour tissues. Mechanistically, Linc00942 recruits RNA methyltransferase METTL3 to stimulate N6‐methyladenosine (m6A) deposit on DNMT3a transcripts, triggering IGF2BP3/HuR to recognize modified mRNA for reinforced stability. SQSTM1/p62 recruits Linc00942 for autophagic degradation which can be abrogated after autophagy inhibition by p62 knockdown or chloroquine treatment. Conclusions Inhibition of autophagy increases Linc00942 expression to promote chemoresistance and autophagy activation or hypomethylating agent decitabine restores chemosensitivity by reducing global DNA methylation. Overall, this study identifies a novel methylation cascade linking impaired RNautophagy to global hypermethylation in chemoresistance, and provides a rationale for repurposing decitabine to overcome chemoresistance in cancer treatment.https://doi.org/10.1002/ctm2.1337chemoresistanceDNMT3aLinc00942N6‐methyladenosineRNautophagy |
| spellingShingle | Liyuan Zhu Yiran Zhu Fang Li Yuan Meng Hanying Wang Wenxia Xu Jingfeng Luo Xian Wang Lifeng Feng Hongchuan Jin RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer Clinical and Translational Medicine chemoresistance DNMT3a Linc00942 N6‐methyladenosine RNautophagy |
| title | RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer |
| title_full | RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer |
| title_fullStr | RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer |
| title_full_unstemmed | RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer |
| title_short | RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer |
| title_sort | rnautophagic regulation of dnmt3a dependent dna methylation by linc00942 enhances chemoresistance in gastric cancer |
| topic | chemoresistance DNMT3a Linc00942 N6‐methyladenosine RNautophagy |
| url | https://doi.org/10.1002/ctm2.1337 |
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