title: cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth.
abstract: The LKB1 tumor suppressor gene is frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP-responsive element-binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.
authors.forename: Zirong
authors.initials: Z
authors.lastname: Chen
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Shuibin
authors.initials: S
authors.lastname: Lin
authors.forename: Chunxia
authors.initials: C
authors.lastname: Cao
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Gimbrone
authors.forename: Rongqiang
authors.initials: R
authors.lastname: Yang
authors.forename: Dongtao A
authors.initials: DA
authors.lastname: Fu
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Carper
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
mesh_terms: D000072283:A549 Cells; D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005819:Genetic Markers; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D005819:Genetic Markers; C000622483:LINC00473 RNA, human; D062085:RNA, Long Noncoding; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases