2. Academic Validation
  3. Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

  • Cancers (Basel). 2020 Mar 3;12(3):580. doi: 10.3390/cancers12030580.
Emilia Białopiotrowicz 1,  Monika Noyszewska-Kania 1,  Neli Kachamakova-Trojanowska 2 3,  Agnieszka Łoboda 2,  Magdalena Cybulska 4,  Aleksandra Grochowska 4,  Michał Kopczyński 4,  Michał Mikula 4,  Monika Prochorec-Sobieszek 5,  Małgorzata Firczuk 6,  Agnieszka Graczyk-Jarzynka 6,  Radosław Zagożdżon 7,  Adam Ząbek 8,  Piotr Młynarz 8,  Józef Dulak 2,  Patryk Górniak 1,  Maciej Szydłowski 1,  Karolina Pyziak 9,  Justyna Martyka 9,  Agnieszka Sroka-Porada 9,  Ewa Jabłońska 1,  Anna Polak 1,  Piotr Kowalczyk 9,  Anna Szumera-Ciećkiewicz 5,  Bjoern Chapuy 10,  Tomasz Rzymski 9,  Krzysztof Brzózka 9,  Przemysław Juszczyński 1
Affiliations

Affiliations

  • 1 Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland.
  • 2 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, 30-387 Cracow, Poland.
  • 3 Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Cracow, Poland.
  • 4 Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.
  • 5 Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland.
  • 6 Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland.
  • 7 Department of Clinical Immunology, Medical University of Warsaw, 02-006 Warsaw, Poland.
  • 8 Department of Bioorganic Chemistry, Wroclaw University of Technology, 50-370 Wroclaw, Poland.
  • 9 Ryvu Therapeutics S.A., 30-348 Cracow, Poland.
  • 10 Department of Hematology and Oncology, University Medical Center Göttingen, 37-075 Göttingen, Germany.
PMID: 32138178 DOI: 10.3390/cancers12030580
Abstract

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in Apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain Amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased Reactive Oxygen Species abundance, and induced Apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent Histone Methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast Cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.

Keywords

Burkitt lymphoma; MYC; metabolism; serine biosynthesis pathway.

Figures
Products