Białopiotrowicz Emilia, Noyszewska-Kania Monika, Kachamakova-Trojanowska Neli, Łoboda Agnieszka, Cybulska Magdalena, Grochowska Aleksandra, Kopczyński Michał, Mikula Michał, Prochorec-Sobieszek Monika, Firczuk Małgorzata, Graczyk-Jarzynka Agnieszka, Zagożdżon Radosław, Ząbek Adam, Młynarz Piotr, Dulak Józef, Górniak Patryk, Szydłowski Maciej, Pyziak Karolina, Martyka Justyna, Sroka-Porada Agnieszka, Jabłońska Ewa, Polak Anna, Kowalczyk Piotr, Szumera-Ciećkiewicz Anna, Chapuy Bjoern, Rzymski Tomasz, Brzózka Krzysztof, Juszczyński Przemysław
Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland.
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, 30-387 Cracow, Poland.
Cancers (Basel). 2020 Mar 3;12(3):580. doi: 10.3390/cancers12030580.
Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The 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 , , and 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.
伯基特淋巴瘤（BL）是一种生长迅速的肿瘤，其特点是合成代谢需求高。原癌基因在这种恶性肿瘤的发病机制中起核心作用，控制着参与细胞凋亡、增殖和细胞代谢的基因。丝氨酸生物合成途径（SBP）将糖酵解与叶酸和甲硫氨酸循环相耦合，支持某些氨基酸、核苷酸、谷胱甘肽和甲基供体S-腺苷甲硫氨酸（SAM）的生物合成。我们报告称，BL中丝氨酸生物合成途径的酶——磷酸甘油酸脱氢酶（PHGDH）和磷酸丝氨酸氨基转移酶1（PSAT1）过表达。这两个基因均受MYC依赖的ATF4转录因子调控。对PHGDH/PSAT1进行基因敲除或用NCT-503对PHGDH进行化学抑制，均可降低BL细胞系的增殖和克隆形成能力。NCT-503降低了谷胱甘肽水平，增加了活性氧的丰度，并诱导细胞凋亡。与SAM作为甲基供体一致，NCT-503降低了DNA和组蛋白甲基化水平，并导致肿瘤抑制因子、、和重新表达。已知H3K27me3水平高会抑制MYC负调控因子miR-494。NCT-503降低了H3K27me3丰度，增加了miR-494水平，并降低了MYC和MYC依赖的组蛋白甲基转移酶EZH2的表达。令人惊讶的是，丝氨酸生物合成途径的化学/基因破坏并未延缓BL和乳腺癌异种移植瘤的生长，这表明体内存在补偿PHGDH/PSAT1缺失的机制。
