title: KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer.
abstract: 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.
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Jandee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Mi-Youn
authors.initials: MY
authors.lastname: Seol
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Seonhyang
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Hyeong Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Cho Rok
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Cheol Ryong
authors.initials: CR
authors.lastname: Ku
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Jong Ju
authors.initials: JJ
authors.lastname: Jeong
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Dong Yeob
authors.initials: DY
authors.lastname: Shin
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea.
authors.forename: Woong Youn
authors.initials: WY
authors.lastname: Chung
authors.affiliation: Departments of SurgeryInternal MedicinePathologyYonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 120-752 Seoul, Korea joys@yuhs.ac.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: connector enhancer of KSR (CNKSR); kinase suppressor of RAS (KSR); notch signaling; oxidative phosphorylation; thyroid cancer