KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway
Abstract Background N 6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the...
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-023-00445-w |
| _version_ | 1797840901602541568 |
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| author | Xiaomin Chen Tiange Lu Yiqing Cai Yang Han Mengfei Ding Yurou Chu Xiangxiang Zhou Xin Wang |
| author_facet | Xiaomin Chen Tiange Lu Yiqing Cai Yang Han Mengfei Ding Yurou Chu Xiangxiang Zhou Xin Wang |
| author_sort | Xiaomin Chen |
| collection | DOAJ |
| description | Abstract Background N 6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. Methods The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Results Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes. Conclusions Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression. |
| first_indexed | 2024-04-09T16:22:24Z |
| format | Article |
| id | doaj.art-14a6d86a7f8f4d239e8def85ec0dda83 |
| institution | Directory Open Access Journal |
| issn | 1689-1392 |
| language | English |
| last_indexed | 2024-04-09T16:22:24Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj.art-14a6d86a7f8f4d239e8def85ec0dda832023-04-23T11:23:31ZengBMCCellular & Molecular Biology Letters1689-13922023-04-0128112910.1186/s11658-023-00445-wKIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathwayXiaomin Chen0Tiange Lu1Yiqing Cai2Yang Han3Mengfei Ding4Yurou Chu5Xiangxiang Zhou6Xin Wang7Department of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityDepartment of Hematology, Shandong Provincial Hospital, Shandong UniversityAbstract Background N 6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. Methods The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Results Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes. Conclusions Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.https://doi.org/10.1186/s11658-023-00445-wDiffuse large B-cell lymphomaN 6-methyladenosineKIAA1429YTHDF2CHST11Hippo–YAP |
| spellingShingle | Xiaomin Chen Tiange Lu Yiqing Cai Yang Han Mengfei Ding Yurou Chu Xiangxiang Zhou Xin Wang KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway Cellular & Molecular Biology Letters Diffuse large B-cell lymphoma N 6-methyladenosine KIAA1429 YTHDF2 CHST11 Hippo–YAP |
| title | KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway |
| title_full | KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway |
| title_fullStr | KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway |
| title_full_unstemmed | KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway |
| title_short | KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway |
| title_sort | kiaa1429 mediated m6a modification of chst11 promotes progression of diffuse large b cell lymphoma by regulating hippo yap pathway |
| topic | Diffuse large B-cell lymphoma N 6-methyladenosine KIAA1429 YTHDF2 CHST11 Hippo–YAP |
| url | https://doi.org/10.1186/s11658-023-00445-w |
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