2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors

      research-article

      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

          Background

          Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer.

          Methods

          We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis.

          Results

          We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions. We experimentally characterized the dual function of two genes, DNAJC9 and HSPA14, in lung cancer cells. We further demonstrated the generalization of this dual direction of associations between HSPs and cancer hallmarks, suggesting the necessity to more carefully evaluate HSPs as therapeutic targets and develop highly specific HSP inhibitors for cancer intervention.

          Conclusions

          Our study furnishes a holistic view of functional associations of HSPs with cancer hallmarks to aid the development of HSP inhibitors as well as other drugs in cancer therapy.

          Related collections

          Most cited references36

          • Record: found
          • Abstract: found
          • Article: found

          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The Molecular Signatures Database (MSigDB) hallmark gene set collection.

            The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of "hallmark" gene sets as part of MSigDB. Each hallmark in this collection consists of a "refined" gene set, derived from multiple "founder" sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

              SUMMARY We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
                Bookmark

                Author and article information

                Contributors
                ldiao@mdanderson.org
                yubinzhou@tamu.edu
                leng.han@uth.tmc.edu
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                23 November 2020
                23 November 2020
                2020
                : 12
                : 101
                Affiliations
                [1 ]GRID grid.267308.8, ISNI 0000 0000 9206 2401, Department of Biochemistry and Molecular Biology, , McGovern Medical School at The University of Texas Health Science Center at Houston, ; Houston, TX 77030 USA
                [2 ]GRID grid.264756.4, ISNI 0000 0004 4687 2082, Center for Translational Cancer Research, Institute of Biosciences and Technology, , Texas A&M University, ; Houston, TX 77030 USA
                [3 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Molecular and Cellular Oncology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                [4 ]GRID grid.267308.8, ISNI 0000 0000 9206 2401, Department of Pediatrics, , McGovern Medical School at The University of Texas Health Science Center at Houston, ; Houston, TX 77030 USA
                [5 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Bioinformatics and Computational Biology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                Author information
                http://orcid.org/0000-0002-7380-2640
                Article
                795
                10.1186/s13073-020-00795-6
                7682077
                33225964
                47958a06-c421-4d6b-9558-ac53595a9675
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 4 April 2020
                : 30 October 2020
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Molecular medicine
                Molecular medicine

                Comments

                Comment on this article