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KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer.

 Jandee Lee  ;  Mi Youn Seol  ;  Seonhyang Jeong  ;  Hyeong Ju Kwon  ;  Cho Rok Lee  ;  Cheol Ryong Ku  ;  Sang Wook Kang  ;  Jong Ju Jeong  ;  Dong Yeob Shin  ;  Kee Hyun Nam  ;  Eun Jig Lee  ;  Woong Youn Chung  ;  Young Suk Jo 
 Journal of Molecular Endocrinology, Vol.54(2) : 115-124, 2015 
Journal Title
 Journal of Molecular Endocrinology 
Issue Date
Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P<0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal P=0.019, false discovery rate (FDR) q-value=0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (ρ=0.677, P=6.15×10(-9)). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal P=0.0097, FDR q-value=0.154 and CNKSR1: nominal P<0.0001, FDR q-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P<0.0001, FDR q-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
강상욱(Kang, Sang Wook) ORCID logo https://orcid.org/0000-0001-5355-833X
구철룡(Ku, Cheol Ryong) ORCID logo https://orcid.org/0000-0001-8693-9630
권형주(Kwon, Hyeong Ju)
남기현(Nam, Kee Hyun) ORCID logo https://orcid.org/0000-0002-6852-1190
설미연(Seol, Mi Youn)
신동엽(Shin, Dong Yeob) ORCID logo https://orcid.org/0000-0003-1048-7978
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
이잔디(Lee, Jan Dee) ORCID logo https://orcid.org/0000-0003-4090-0049
이초록(Lee, Cho Rok) ORCID logo https://orcid.org/0000-0001-7848-3709
정선향(Jeong, Seonhyang) ORCID logo https://orcid.org/0000-0002-5549-9182
정웅윤(Chung, Woung Youn)
정종주(Jeong, Jong Ju) ORCID logo https://orcid.org/0000-0002-4155-6035
조영석(Jo, Young Suk) ORCID logo https://orcid.org/0000-0001-9926-8389
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