Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our resul...

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Published in:Molecular carcinogenesis 2024-07, Vol.63 (7), p.1334-1348
Main Authors: Zhang, Shaoting, Zhang, Liangying, Zhang, Dan, Guo, Yue, Gao, Yisha, Jiang, Zongying, Li, Shujing, Liu, Anbu, Cao, Xu, Tian, Jinhai, Zhao, Sien, Yu, Yuanyuan, Yang, Wei, Bai, Ru, Huang, Ling, Yan, Hongli, Zhao, Hui, Sun, Jianmin
Format: Article
Language:English
Subjects:
Animal research
FHL2
FHL2 protein
Gastric cancer
Gastrointestinal cancer
Gene expression
GIST
Imatinib
Mutants
mutation
Targeted cancer therapy
Tumorigenesis
Tumors
Ubiquitination
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Summary:Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild‐type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild‐type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first‐line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild‐type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug‐resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.
ISSN:0899-1987
1098-2744
1098-2744
DOI:10.1002/mc.23727