Why is cancer so deadly? These proteins have to work!

June 11, 2019 / bioun / - this issue reviews the latest research progress on cancer-related proteins, helping you understand the important role of cancer-related proteins in the process of cancer occurrence, development, metastasis and recurrence, and how new discoveries on cancer-related proteins can help us improve cancer treatment and diagnosis strategies 【1】 Science subjournal: discovery of the new role of frequently mutated oncoprotein in space chromosome tissue doi: 10.1126/sciadv.aaw5294 a new study by the Westar Institute revealed the function of protein arid1a, which is encoded by a gene, which is one of the most common mutations in human cancer According to the study published in science advanced, arid1a plays a role in the spatial organization of the genome; therefore, its deletion has a wide influence on the overall gene expression This discovery provides important information for deciphering molecular changes related to several cancers, especially ovarian cancer Photo source: the three-dimensional structure of science advanced genome determines how DNA molecules accumulate in a micro space, and also allows each gene to be transcribed and expressed at an appropriate time The team found that arid1a interacts with a component of the lectin II complex, which regulates gene expression through tissue chromosome structure The results show that arid1a determines the genome location of thrombin II on some DNA regulatory elements called enhancers Therefore, when the function of arid1a is lost due to gene mutation, the distribution of prothrombin II changes and the expression of a large number of genes changes Zhang and his colleagues also found that through interaction with prothrombin II, arid1a controls how different parts of the chromosome are spatially organized together, known as chromosomal regions, which contribute to the coordinated expression of certain genes 【2】 Mol Cancer Res: a new study reveals that doi: 10.1158/1541-7786.mcr-18-1279, a protein molecule that causes prostate cancer to deteriorate, researchers at Boston University School of Medicine (BUSM) found that blocking specific proteins may have the effect of preventing the deterioration of malignant prostate cancer (CRPC) Researchers have long studied three closely related protein families, known as bet bromine domain proteins, which are composed of BRD2, BRD3 and Brd4 that regulate gene expression These researchers have now found that the inhibitory protein Brd4 has the ability to regulate the migration and invasion of prostate cancer cells "Our results are very important because the current treatment options for CRPC are limited, mainly focusing on the inhibition of prostate cancer cells that rely on AR signaling," explains Jordan shafran, the first author, PhD, BUSM CRPC is a complex heterogeneous disease with different ar States and expression patterns in various tumor cells With the development of the disease, prostate cancer cells can reduce their dependence on AR signal and use alternative signaling mechanisms to maintain growth and transmission "Therefore, it is necessary to identify 'pharmaceutical' targets that regulate prostate cancer cell migration and invasion, which are dependent on or independent of androgen receptor signaling," he added 【3】 Nature: to reveal that nnmt is the main metabolic regulatory protein of cancer-related fibroblasts doi: 10.1038/s41586-019-1173-8 The systematic investigation of the surrounding tissues, especially the normal cells called fibroblasts, reveals that a new therapeutic target may potentially prevent the rapid spread and prognosis related to hgsc The results were published in the journal Nature In this new study, the researchers found that stroma has an important effect on cancer cells "In this case, it makes them more malignant, more aggressive and more invasive," says Lengyel The matrix is usually larger than the cancer itself "The researchers analyzed the expression of more than 5000 proteins in normal and cancerous tissues from a small sample bank of patients For the first time, they were able to distinguish molecular changes in cancer cells from those in the surrounding matrix as the disease progressed When they got their data, they found that, contrary to cancer cells, metastatic stroma had highly conserved protein characteristics These metastatic changes were observed in all patients analyzed They are now trying to understand their functional role in cancer metastasis in order to find new therapeutic targets In this process, they found a metabolic enzyme, nicotinamide N-methyltransferase (nnmt), which is highly expressed in the matrix around metastatic cancer cells They found that nnmt causes a wide range of gene expression changes in the tumor matrix, thus transforming normal fibroblasts into cancer-related fibroblasts that support and accelerate tumor growth The expression of nnmt in stroma promotes the progression and metastasis of ovarian cancer This is related to very poor patient outcomes The researchers are now using high-throughput screening to find new ways to inhibit the enzyme Co lead author Mark Eckert, assistant professor of Obstetrics and gynecology at the University of Chicago, "one approach looks promising We have several candidate inhibitor skeletons We know our target, we know the structure, how we treat it, we have a sense of direction We began to understand how normal fibroblasts are transformed into cancer-related fibroblasts by this metabolic enzyme [4] Science: scientists found that the protein doi: 10.1126/sciadv.aaw1616, which mediates the key life activities of cancer cells, has the potential to treat cancer by targeting ruvbl1-ruvbl2 Ruvbl1-ruvbl2 is the energy engine accompanying r2tp This allowed researchers from the DNA damage response research group of the National Cancer Research Center (CNIO) in Spain to use powerful frozen electron microscopy tools to determine the mechanism of regulating ruvbl1 and ruvbl2, which was published in the journal science advances Photo source: science advanced as mentioned above, the macromolecular complex research team in DNA damage reaction has determined the high-resolution structure of r2tp with low-temperature electron microscope In this study, CNIO researchers looked at how cells designed r2tp to bring chaperone Hsp90 into contact with the proteins it works on R2tp complex has an energy engine, a ring composed of ATPase ruvbl1 and ruvbl2, which can generate ADP by using the energy released by ATP hydrolysis In this energy production mechanism, ATP enzymes capture ATP in cells and continuously release ADP as waste and energy Scientists found that in the ring formed by ruvbl1 and ruvbl2, the ATP binding site pathway was completely blocked, and ATP or ADP remained in the ring, thus hindering the energy exchange and motor work The question is, how to use the energy needed to assemble protein complexes? By observing the r2tp system under the low-temperature electron microscope, the researchers found the answer: "we found an area in ruvbl2, which serves as a channel to control ATP and ADP to enter the protein; this process requires the energy provided by ATP The key to regulating the opening of this door is the interaction between the r2tp components required for the assembly of ATPase ruvbl2 and mTOR [5] eLife: it is found that the protein doi: 10.7554/elife.41801, which is related to cancer metastasis, is the main working substance of human body, and it almost participates in every process of cells Different types of molecules, such as sugar, can be added to proteins to change their roles or positions, but this process may also play a role in cancer In fact, tumor cells with specific sugar modifications are more likely to spread in the body But so far, researchers don't know whether T antigen promotes this process or just appears on these cells To answer this question, Daria siekhaus and others from the Austrian Institute of science and technology used genetic and biochemical tools to study the developmental stage of Drosophila embryos, some of the immune cells in these embryos carry T-antigen protein Like invasive cancer cells, these immune cells can enter tissues during development Photo source: eLife experiment shows that a protein called Minerva can help T antigen attach to protein When researchers genetically engineered embryos to contain less Minerva, the number of T antigens in immune cells decreased, and cells could not easily enter tissues When mouse derived Minerva is added to the embryo again, the immune cells of Drosophila contain more T antigens, which can invade the tissue again At present, some proteins targeted by Minerva are known to be related to cancer, but not all of them are related to cancer Future experiments will investigate the role of human Minerva in cancer cells entering new tissue and whether it can help us predict whether cancer is likely to spread 【6】 Gene dev: cdk12 protein's new role in cancer progression doi: 10.1101/gad.322339.118 it is well known that metastatic ovarian cancer, prostate cancer and breast cancer are difficult to treat and fatal Now, researchers at the Salk Institute have revealed a new role for cdk12 in the progression of cancer The results were published in the journal genes & development "About 3-5% of prostate, ovarian and breast cancers contain mutations in the cdk12 gene, and recent studies have shown that this subset of cells has a unique response to immunotherapeutic drugs, while most of these cancers do not respond," the authors said "This suggests that for most cancers that lack mutations in cdk12, chemical inhibitors of cdk12 can be used to make them more susceptible to being killed by chemotherapy drugs." Death, and may be more sensitive to immunotherapy "By analyzing the role of cdk12 in protecting cells from chemotherapy, the team found a new set of genes controlled by cdk12, including many regulated by another protein called mTORC1, which controls the metabolism of cancer cells Although cdk12 is mainly located in the nucleus, it, together with mTORC1, controls the translation process - an important step in the production of new proteins in cells In collaboration with Professor Salk, Alan saghatelian, the team was able to identify specific genes regulated by cdk12 at the translation level It is found that hundreds of genes are controlled by cdk12 in this new way, many of which are related to the growth of cancer cells To the researchers' surprise, many other newly discovered cdk12 regulatory genes are crucial for cell division (mitosis) A microscopic imaging study by seunjae Kim, a postdoctoral researcher at Salk, showed that cdk12 helps chromosomes condense and then separate into two different cells The role of cdk12 in the whole gene network expression necessary for mitosis is completely unknown 【7】 Mol Cell: the key protein for cancer development "gas assisted" doi: 10.1016/j.molcel.2019.02.031 the cells that make up our body are quite different, and each cell has a unique function However, the blueprints of each protein are preserved in genes, and our genetic information is the same in every cell of our body For cells with the same genetic material to produce different proteins, some "helper" proteins are necessary The molecules responsible for this help are called transcription factors - these ensure that only specific genes are read and transcribed to produce more of the proteins needed