19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

      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

          Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.

          Abstract

          Centrosome clustering is a promising therapeutic target in cancer but how it is regulated remains unclear. Here, the authors show that in response to DNA damage, ATM/ATR stabilize the centrosome clustering regulator KIFC1 leading to increased clustering efficiency and tumour recurrence.

          Related collections

          Most cited references51

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

          The DNA-damage response in human biology and disease.

          The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Triple-negative breast cancer: clinical features and patterns of recurrence.

            To compare the clinical features, natural history, and outcomes for women with "triple-negative" breast cancer with women with other types of breast cancer. We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P < 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P < 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at approximately 3 years and declined rapidly thereafter. Among the "other" group, the recurrence risk seemed to be constant over the period of follow-up. Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              DNA damage and the balance between survival and death in cancer biology.

              DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage.
                Bookmark

                Author and article information

                Contributors
                spzhang2019@126.com
                cgwang2016@sjtu.edu.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                4 January 2021
                4 January 2021
                2021
                : 12
                : 20
                Affiliations
                [1 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Translational Medicine Center, Shanghai General Hospital, , Shanghai Jiao Tong University School of Medicine, ; 201620 Shanghai, China
                [2 ]Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Shandong First Medical University, 271000 Shandong, China
                [3 ]GRID grid.412449.e, ISNI 0000 0000 9678 1884, Key Laboratory of Medical Cell Biology, College of Translational Medicine, , China Medical University, ; 110000 Shenyang, China
                [4 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Department of Oncology, Karmanos Cancer Institute, , Wayne State University School of Medicine, ; 4100 John R., Detroit, MI 48201 USA
                [5 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Hematology, Shanghai General Hospital, , Shanghai Jiao Tong University School of Medicine, ; 201620 Shanghai, China
                [6 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Urology, Shanghai General Hospital, , Shanghai Jiao Tong University School of Medicine; Institute of Urology, Shanghai Jiao Tong University, ; 200080 Shanghai, China
                [7 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Gastroenterology, Shanghai General Hospital, , Shanghai Jiao Tong University School of Medicine, ; 201620 Shanghai, China
                Author information
                http://orcid.org/0000-0003-0684-1380
                http://orcid.org/0000-0003-4088-2768
                http://orcid.org/0000-0002-1213-946X
                Article
                20208
                10.1038/s41467-020-20208-x
                7782532
                33397932
                6810c47a-7715-42d9-b696-90fb8c5e63d1
                © The Author(s) 2021

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 1 February 2020
                : 18 November 2020
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Uncategorized
                cancer therapy,mitosis,phosphorylation
                Uncategorized
                cancer therapy, mitosis, phosphorylation

                Comments

                Comment on this article