Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer.

Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.

[Imaging port wine stain by optical coherence tomography].

Optical coherence tomography is an appropriate imaging method for biomedical science, due to its advantages of noninvasive nature, high resolution and fast imaging speed. Because most biological tissues have the characteristic of high scattering coefficient, OCT system can just obtain the structural images several millimeters below the surface of the tissues. The superficial depth of OCT's penetration limits application in dermatology field. As a common disease, the port wine stain (PWS) is a indication of OCT, because of its superficial lesion and significant expansion of blood vessels. To get deeper penetration in the skin, the authors employed 1 310 nm superluminescent diode as light source, optimized the light intensity ratio of reference delay arm and sample arm and control polarization, and the research of PWS imaging in vivo was accomplished. Besides, OCT is able to gather clear image and key characteristic parameters, such as the depth of epidermis layer, the diameter of blood vessel, etc. OCT will play an important role in the diagnosis and therapy of PWS.

Effects of MCRS1 on proliferation, migration, invasion, and epithelial mesenchymal transition of gastric cancer cells by interacting with Pkmyt1 protein kinase.

Microspherule protein 1(MCRS1) is known to be an oncogene in several tumors. However, recent studies have shown that MCRS1 inhibits lymphatic metastasis in gastric cancer (GC) patients by inhibiting telomerase activity. Protein kinase, membrane associated tyrosine/threonine 1(Pkmyt1), a member of the WEE1 family, has been found to interact with MCRS1 by yeast two-hybrid assay; however, how these two proteins interact in GC is still unclear. Hence, this study aimed to investigate the effect of MCRS1 interaction with Pkmyt1 on GC cell proliferation, migration, and invasion. Initially, we observed increased expression of MCRS1 in GC SGC-7901 cells and decreased expression in GC BGC-823 cells. Hence, we down-regulated MCRS1 expression in SGC-7901 cells and up-regulated it in BGC-823 cells. Our results showed that overexpression of MCRS1 inhibits the growth, invasion and migration of GC cells, while downregulation of MCRS1 promotes the growth, invasion and migration of GC cells. When MK1775, an inhibitor of WEE1 kinase, was added after downregulation of MCRS1, phenotypic recovery effects were observed. Overexpression of MCRS1 also inhibited the expression of Pkmyt1 and vice versa. This indicated that there might be a possible interaction between MCRS1 and Pkmyt1. Furthermore, immunoprecipitation assay revealed the interaction between MCRS1 and Pkmyt1 in virto, and immunofluorescence experiments showed that the two proteins were co-localized in the cytoplasm. In conclusion, our study confirmed the specific tumor suppressive activity of MCRS1 in GC proliferation, invasion and migration and suggested that it might inhibit the progression of GC through its interaction with Pkmyt1.

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation.

Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations.