PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells
Yi Yang
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
*Y.Y. and J.W. contributed equally to this work
Search for more papers by this authorJueheng Wu
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
*Y.Y. and J.W. contributed equally to this work
Search for more papers by this authorJunchao Cai
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorZhenjian He
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorJie Yuan
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Education of Guangdong Province, Key Laboratory of Functional Molecules from Oceanic Microorganisms, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorXun Zhu
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorYanbing Li
Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080 China
Search for more papers by this authorCorresponding Author
Mengfeng Li
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Correspondence to: Hongyu Guan, Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87335868, Fax: +86 (20) 87331209, E-mail: [email protected] or Mengfeng Li, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87332748, Fax: +86 (20) 87331209, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Hongyu Guan
Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080 China
Correspondence to: Hongyu Guan, Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87335868, Fax: +86 (20) 87331209, E-mail: [email protected] or Mengfeng Li, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87332748, Fax: +86 (20) 87331209, E-mail: [email protected]Search for more papers by this authorYi Yang
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
*Y.Y. and J.W. contributed equally to this work
Search for more papers by this authorJueheng Wu
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
*Y.Y. and J.W. contributed equally to this work
Search for more papers by this authorJunchao Cai
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorZhenjian He
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorJie Yuan
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Education of Guangdong Province, Key Laboratory of Functional Molecules from Oceanic Microorganisms, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorXun Zhu
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Search for more papers by this authorYanbing Li
Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080 China
Search for more papers by this authorCorresponding Author
Mengfeng Li
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080 China
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080 China
Correspondence to: Hongyu Guan, Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87335868, Fax: +86 (20) 87331209, E-mail: [email protected] or Mengfeng Li, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87332748, Fax: +86 (20) 87331209, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Hongyu Guan
Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080 China
Correspondence to: Hongyu Guan, Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87335868, Fax: +86 (20) 87331209, E-mail: [email protected] or Mengfeng Li, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China, Tel.: +86(20)87332748, Fax: +86 (20) 87331209, E-mail: [email protected]Search for more papers by this authorAbstract
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.
Abstract
What's new?
Metabolic enzymes play key regulatory roles in tumorigenesis, though their specific contributions to tumor cell growth and survival are unclear. This report is the first to demonstrate that phosphoserine aminotransferase 1 (PSAT1), an enzyme involved in serine biosynthesis, is overexpressed in non-small cell lung cancer (NSCLC). Elevated PSAT1 appears to enhance the proliferation of NSCLC cells by promoting cell-cycle progression, an effect associated with inhibition of cyclin D1 degradation and altered activity of the Rb-E2F pathway. The results indicate that unrestrained cell-cycle progression in NSCLC is linked to PSAT1 upregulation and constitutive activation of E2F.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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