A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
|---|---|
| Enthalten in: |
Cell reports - 43(2024), 4 vom: 23. Apr., Seite 114032 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cao, Lei [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 26.04.2024 Date Revised 27.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.celrep.2024.114032 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370582330 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370582330 | ||
| 003 | DE-627 | ||
| 005 | 20240427232219.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240404s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.celrep.2024.114032 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1390.xml |
| 035 | |a (DE-627)NLM370582330 | ||
| 035 | |a (NLM)38568805 | ||
| 035 | |a (PII)S2211-1247(24)00360-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cao, Lei |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.04.2024 | ||
| 500 | |a Date Revised 27.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CP: Cancer | |
| 650 | 7 | |a LATS2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.1.11 |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a AlkB Homolog 5, RNA Demethylase |2 NLM | |
| 650 | 7 | |a EC 1.14.11.- |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 650 | 7 | |a ALKBH5 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.11.- |2 NLM | |
| 650 | 7 | |a Adenosine |2 NLM | |
| 650 | 7 | |a K72T3FS567 |2 NLM | |
| 650 | 7 | |a N-methyladenosine |2 NLM | |
| 650 | 7 | |a CLE6G00625 |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 700 | 1 | |a Han, Ruohui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yingying |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Xiaoyang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ziyi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zexing |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Xiujuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Dayong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Baofeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xudong |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell reports |d 2012 |g 43(2024), 4 vom: 23. Apr., Seite 114032 |w (DE-627)NLM217067492 |x 2211-1247 |7 nnns |
| 773 | 1 | 8 | |g volume:43 |g year:2024 |g number:4 |g day:23 |g month:04 |g pages:114032 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.celrep.2024.114032 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 43 |j 2024 |e 4 |b 23 |c 04 |h 114032 | ||