Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors

Oncogene
Yuan-Shuo HsuehLi-Tzong Chen

Abstract

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viab...Continue Reading

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Citations

Oct 9, 2020·Signal Transduction and Targeted Therapy·Xiaoling SongYingbin Liu
Aug 12, 2021·Molecular Cancer Therapeutics·Sudeep BanerjeeJason K Sicklick

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Methods Mentioned

BETA
immunoprecipitation
ChIP-seq
PCR
confocal microscopy
nuclear translocation
ChIP
xenograft
xenografts

Software Mentioned

Statistical Package for the Social Sciences
ChIP
MEME

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