PMID- 37515378
OWN - NLM
STAT- MEDLINE
DCOM- 20231011
LR  - 20231011
IS  - 2198-3844 (Electronic)
IS  - 2198-3844 (Linking)
VI  - 10
IP  - 27
DP  - 2023 Sep
TI  - HSP90beta Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib 
      Resistance in Hepatocellular Carcinoma.
PG  - e2302025
LID - 10.1002/advs.202302025 [doi]
LID - 2302025
AB  - YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m(6) A) 
      reader that regulates the status of mRNA. It has been reported that overexpressed 
      YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) 
      is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict 
      poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the 
      upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90beta) and 
      STIP1 homology and U-box-containing protein 1 (STUB1) physically interact with 
      YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of 
      HSP90beta is required for its interaction with STUB1 and YTHDF2. HSP90beta inhibits the 
      STUB1-induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to 
      further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90beta 
      and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The 
      expression of HSP90beta is positively correlated with the YTHDF2 protein level, 
      whereas the expression of STUB1 is negatively correlated with the protein levels 
      of YTHDF2 and HSP90beta. These findings deepen the understanding of how YTHDF2 is 
      regulated to drive HCC progression and provide potential targets for treating 
      HCC.
CI  - (c) 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
FAU - Liao, Yuning
AU  - Liao Y
AD  - Affiliated Cancer Hospital & institute of Guangzhou Medical University, 
      Guangzhou, 510095, China.
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Liu, Yuan
AU  - Liu Y
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Yu, Cuifu
AU  - Yu C
AD  - Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, 
      516600, China.
FAU - Lei, Qiucheng
AU  - Lei Q
AD  - Department of Hepatopancreatic Surgery, The First People's Hospital of Foshan, 
      Foshan, 528000, China.
FAU - Cheng, Ji
AU  - Cheng J
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Kong, Weiyao
AU  - Kong W
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Yu, Yuanhui
AU  - Yu Y
AD  - KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 
      511436, China.
FAU - Zhuang, Xuefen
AU  - Zhuang X
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Sun, Wenshuang
AU  - Sun W
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Yin, Shusha
AU  - Yin S
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
FAU - Cai, Gengxi
AU  - Cai G
AD  - Department of Breast Surgery, The First People's Hospital of Foshan, Foshan, 
      528000, China.
FAU - Huang, Hongbiao
AU  - Huang H
AUID- ORCID: 0000-0002-9873-0559
AD  - Affiliated Cancer Hospital & institute of Guangzhou Medical University, 
      Guangzhou, 510095, China.
AD  - Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein 
      Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical 
      University, Guangzhou, 511436, China.
LA  - eng
GR  - 82002481/National Natural Science Foundation of China/
GR  - 82072810/National Natural Science Foundation of China/
GR  - 2220001003854/Science and technology innovation project of Foshan/
GR  - 2220001004847/Science and technology innovation project of Foshan/
GR  - JP2022002/Cultivation Program of National Natural Science Foundation for 
      Distinguished Young Scholars of Guangzhou Medical University/
GR  - scientific research in Guangzhou Medical University/
GR  - 2022KCXTD021/Universities in Guangdong Province/
GR  - JCXKJS2022A06/Guangzhou Medical University/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230728
PL  - Germany
TA  - Adv Sci (Weinh)
JT  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
JID - 101664569
RN  - 0 (RNA-Binding Proteins)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 2.3.2.27 (STUB1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - 0 (YTHDF2 protein, human)
RN  - 0 (HSP90 Heat-Shock Proteins)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Hepatocellular/drug therapy/metabolism
MH  - *Liver Neoplasms/drug therapy/genetics/metabolism
MH  - RNA-Binding Proteins/metabolism
MH  - Sorafenib/pharmacology
MH  - Ubiquitin-Protein Ligases/genetics
MH  - Ubiquitination
MH  - Up-Regulation
MH  - *HSP90 Heat-Shock Proteins/metabolism
PMC - PMC10520652
OTO - NOTNLM
OT  - HSP90beta
OT  - STUB1
OT  - YTHDF2
OT  - hepatocellular carcinoma
OT  - ubiquitination
COIS- The authors declare no conflict of interest.
EDAT- 2023/07/29 11:50
MHDA- 2023/10/04 06:43
PMCR- 2023/07/28
CRDT- 2023/07/29 02:45
PHST- 2023/07/06 00:00 [revised]
PHST- 2023/03/29 00:00 [received]
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/07/29 11:50 [pubmed]
PHST- 2023/07/29 02:45 [entrez]
PHST- 2023/07/28 00:00 [pmc-release]
AID - ADVS6178 [pii]
AID - 10.1002/advs.202302025 [doi]
PST - ppublish
SO  - Adv Sci (Weinh). 2023 Sep;10(27):e2302025. doi: 10.1002/advs.202302025. Epub 2023 
      Jul 28.