title: PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells.
abstract: Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss- and gain-of-function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3β was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK-3β phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3β, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Li
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Guan
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D015398:Signal Transduction; D000637:Transaminases / Q000502:physiology*; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: C530104:CCND1 protein, human; D050684:E2F Transcription Factors; D019938:Cyclin D1; D000637:Transaminases; C022393:phosphoserine aminotransferase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3β; PSAT1; cyclin D1; non-small cell lung cancer; proliferation