Blog
About

1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

      1 , 2 , 3 , 3 , 3 , 2 , 2 , 3 , 3 , 2 , 3 , 2 , 2 , 3 , 2 , 3 , 3 , 3 , 1 , 2 , 4 , 2 , 3 , 3 , 5 , 1 , 2 , 1 , 1 , 2 , 3 , 1 , 2 , 4 , 4 , 2 , 1 , 2 , 3 , 3 , 3 , 3 , 2 , 1 , 2 , 1 , 2 , 6 , 2 , 3 , 2 , 3 , 7 , 2 , 3 , 7 , 3 , , 2 , 3 , 7

      ,

      eLife

      eLife Sciences Publications, Ltd

      renal medullary carcinoma, SMARCB1, MLN2238, ubiquitin-proteasome system, cell cycle, Human

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.

          eLife digest

          Renal medullary carcinoma (RMC for short) is a rare type of kidney cancer that affects teenagers and young adults. These patients are usually of African descent and carry one of the two genetic changes that cause sickle cell anemia. RMC is an aggressive disease without effective treatments and patients survive, on average, for only six to eight months after their diagnosis.

          Recent genetic studies found that most RMC cells have mutations that prevent them from producing a protein called SMARCB1. SMARCB1 normally acts as a so-called tumor suppressor, preventing cells from becoming cancerous. However, it was not clear whether RMCs always have to lose SMARCB1 if they are to survive and grow.

          Often, diseases are studied using laboratory-grown cells and tissues that have certain features of the disease. No such models had been created for RMC, which has slowed efforts to understand how the disease develops and find new treatments for it. Hong et al. therefore worked with patients to develop new lines of cells that can be used to study RMC in the laboratory. These RMC cells started dying when they were given copies of the SMARCB1 gene, which supports the theory that RMCs have to lose SMARCB1 in order to grow.

          Hong et al. then used a set of genetic reagents that can suppress or delete genes that are targeted by drugs, and followed this by testing a range of drugs on the RMC cells. Drugs and genetic reagents that reduced the activity of the proteasome – the structure inside cells that gets rid of old or unwanted proteins – caused the RMC cells to die. These proteasome inhibitor drugs also killed other kinds of cancer cells with SMARCB1 mutations.

          Proteasome inhibitors are already used to treat different types of cancer. Potentially, a clinical trial could be run to see if they will treat patients whose cancers lack SMARCB1. Further work is also needed to determine the exact link between SMARCB1 and the proteasome.

          Related collections

          Most cited references 54

          • Record: found
          • Abstract: found
          • Article: not found

          Creation of human tumour cells with defined genetic elements.

          During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization, the selection of rare, spontaneously arising immortalized cells, or the use of an entire viral genome. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1.

            CDK1 is a nonredundant cyclin-dependent kinase (CDK) with an essential role in mitosis, but its multiple functions still are poorly understood at a molecular level. Here we identify a selective small-molecule inhibitor of CDK1 that reversibly arrests human cells at the G(2)/M border of the cell cycle and allows for effective cell synchronization in early mitosis. Inhibition of CDK1 during cell division revealed that its activity is necessary and sufficient for maintaining the mitotic state of the cells, preventing replication origin licensing and premature cytokinesis. Although CDK1 inhibition for up to 24 h is well tolerated, longer exposure to the inhibitor induces apoptosis in tumor cells, suggesting that selective CDK1 inhibitors may have utility in cancer therapy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.

              Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein kinase growth signaling in MM cells; induces apoptosis despite induction of p21 and p27 in both p53 wild-type and p53 mutant MM cells; overcomes drug resistance; adds to the anti-MM activity of dexamethasone; and overcomes the resistance to apoptosis in MM cells conferred by interleukin-6. PS-341 also inhibits the paracrine growth of human MM cells by decreasing their adherence to bone marrow stromal cells (BMSCs) and related nuclear factor kappaB-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy.
                Bookmark

                Author and article information

                Contributors
                Role: Senior Editor
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                12 March 2019
                2019
                : 8
                Affiliations
                [1 ]Boston Children’s Hospital BostonUnited States
                [2 ]Dana-Farber Cancer Institute BostonUnited States
                [3 ]Broad Institute of Harvard and MIT CambridgeUnited States
                [4 ]Rare Cancer Research Foundation DurhamUnited States
                [5 ]RMC Support North CharlestonUnited States
                [6 ]St. Jude Children’s Research Hospital MemphisUnited States
                [7 ]Brigham and Women’s Hospital BostonUnited States
                Calico Life Sciences United States
                Memorial Sloan Kettering Cancer Center United States
                Memorial Sloan Kettering Cancer Center United States
                Memorial Sloan Kettering Cancer Center United States
                UT Southwestern Medical Center United States
                Article
                44161
                10.7554/eLife.44161
                6436895
                30860482
                © 2019, Hong et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100001445, Alex's Lemonade Stand Foundation for Childhood Cancer;
                Award ID: Young Investigator Award
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000043, American Association for Cancer Research;
                Award ID: 14-40-31-HONG
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000048, American Cancer Society;
                Award ID: 132943-MRSG-18-202-01-TBG
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006823, Boston Children's Hospital;
                Award ID: OFD BTREC CDA
                Award Recipient :
                Funded by: Cure AT/RT;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006315, CureSearch for Children's Cancer;
                Award ID: 328545
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007886, Dana-Farber Cancer Institute;
                Award ID: Wong Family Award
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;
                Award ID: K12 HD052896
                Award Recipient :
                Funded by: Katie Moore Foundation;
                Award Recipient :
                Funded by: Merkin Family Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: U01 CA176058
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: U01 CA217848
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: P50 CA101942
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: T32 GM007753
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: T32 GM007226
                Award Recipient :
                Funded by: Team Path to Cure;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000005, U.S. Department of Defense;
                Award ID: W81XWH-15-1-0659
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cancer Biology
                Human Biology and Medicine
                Custom metadata
                Faithful models of RMC require SMARCB1 loss for survival, and genetic and small-molecule screens identify inhibition of the ubiquitin-proteasome system (UPS) as a potential therapeutic approach for SMARCB1 deficient cancers.

                Life sciences

                cell cycle, human, smarcb1, mln2238, ubiquitin-proteasome system, renal medullary carcinoma

                Comments

                Comment on this article