SPANX Control of Lamin A/C Modulates Nuclear Architecture and Promotes Melanoma Growth

Mechanisms regulating nuclear organization control fundamental cellular processes, including the cell and chromatin organization. Their disorganization, including aberrant nuclear architecture, has been often implicated in cellular transformation. Here, we identify Lamin A, among proteins essential for nuclear architecture, as SPANX (sperm protein associated with the nucleus on the X chromosome), a cancer testis antigen previously linked to invasive tumor phenotypes, interacting protein in melanoma. SPANX interaction with Lamin A was mapped to the immunoglobulin fold-like domain, a region critical for Lamin A function, which is often mutated in laminopathies. SPANX downregulation in melanoma cell lines perturbed nuclear organization, decreased cell viability, and promoted senescence-associated phenotypes. Moreover, SPANX knockdown (KD) in melanoma cells promoted proliferation arrest, a phenotype mediated in part by IRF3/IL1A signaling. SPANX KD in melanoma cells also prompted the secretion of IL1A, which attenuated the proliferation of naïve melanoma cells. Identification of SPANX as a nuclear architecture complex component provides an unexpected insight into the regulation of Lamin A and its importance in melanoma. Implications: SPANX, a testis protein, interacts with LMNA and controls nuclear architecture and melanoma growth.

[1]  E. Ruppin,et al.  Regulation of eIF2α by RNF4 promotes melanoma tumorigenesis and therapy resistance. , 2020, The Journal of investigative dermatology.

[2]  Ying Wang,et al.  A rare subpopulation of melanoma cells with low expression of metastasis suppressor NME1 is highly metastatic in vivo , 2020, Scientific Reports.

[3]  C. Garrido,et al.  Heat-shock proteins: chaperoning DNA repair , 2019, Oncogene.

[4]  A. Ciechanover,et al.  Identification of proteins regulated by the proteasome following induction of endoplasmic reticulum stress. , 2019, Biochemical and biophysical research communications.

[5]  Elizabeth R. Smith,et al.  Defective Nuclear Lamina in Aneuploidy and Carcinogenesis , 2018, Front. Oncol..

[6]  D. Dorsett,et al.  A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin , 2018, Cell reports.

[7]  Samuel F. Bakhoum,et al.  Chromosomal instability drives metastasis through a cytosolic DNA response , 2017, Nature.

[8]  R. Golsteyn,et al.  G2/M-Phase Checkpoint Adaptation and Micronuclei Formation as Mechanisms That Contribute to Genomic Instability in Human Cells , 2017, International journal of molecular sciences.

[9]  K. Kaestner,et al.  Cytoplasmic chromatin triggers inflammation in senescence and cancer , 2017, Nature.

[10]  H. Funabiki,et al.  The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death , 2019, Cell.

[11]  Dennis E Discher,et al.  Mitotic progression following DNA damage enables pattern recognition within micronuclei , 2017, Nature.

[12]  Zhijian J. Chen,et al.  Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing , 2016, Nature Immunology.

[13]  Hsuan-Yu Chen,et al.  SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma , 2016, Oncotarget.

[14]  M. C. Cardoso,et al.  RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA , 2016, Nature Communications.

[15]  Jill M. Westcott,et al.  The cancer-testis antigens SPANX-A/C/D and CTAG2 promote breast cancer invasion , 2016, Oncotarget.

[16]  G. Mills,et al.  Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies , 2015, Clinical Cancer Research.

[17]  T. Shibata,et al.  SRY and OCT4 Are Required for the Acquisition of Cancer Stem Cell‐Like Properties and Are Potential Differentiation Therapy Targets , 2015, Stem cells.

[18]  Q. Jiang,et al.  The lamin-A/C–LAP2α–BAF1 protein complex regulates mitotic spindle assembly and positioning , 2015, Journal of Cell Science.

[19]  P. Nelson,et al.  MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation , 2015, Nature Cell Biology.

[20]  R. Foisner,et al.  Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. , 2015, Annual review of biochemistry.

[21]  R. Dummer,et al.  A new live‐cell biobank workflow efficiently recovers heterogeneous melanoma cells from native biopsies , 2015, Experimental dermatology.

[22]  Sreeparna Banerjee,et al.  Epigenetic Mechanisms Underlying the Dynamic Expression of Cancer-Testis Genes, PAGE2, -2B and SPANX-B, during Mesenchymal-to-Epithelial Transition , 2014, PloS one.

[23]  Triantafyllos Stylianopoulos,et al.  The role of mechanical forces in tumor growth and therapy. , 2014, Annual review of biomedical engineering.

[24]  T. Misteli,et al.  Systematic identification of pathological lamin A interactors , 2014, Molecular biology of the cell.

[25]  Jan Lammerding,et al.  Broken nuclei--lamins, nuclear mechanics, and disease. , 2014, Trends in cell biology.

[26]  Henning Hermjakob,et al.  The Reactome pathway knowledgebase , 2013, Nucleic Acids Res..

[27]  C. Horvath,et al.  Extensive cooperation of immune master regulators IRF3 and NFκB in RNA Pol II recruitment and pause release in human innate antiviral transcription. , 2013, Cell reports.

[28]  T. Deerinck,et al.  Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei , 2013, Cell.

[29]  N. D. Di Paolo,et al.  The transcription factor IRF3 triggers "defensive suicide" necrosis in response to viral and bacterial pathogens. , 2013, Cell reports.

[30]  Y. Gruenbaum,et al.  Lamins in development, tissue maintenance and stress , 2012, EMBO reports.

[31]  E. Benarroch,et al.  Nuclear lamins , 2012, Neurology.

[32]  Anindya Dutta,et al.  p21 in cancer: intricate networks and multiple activities , 2009, Nature Reviews Cancer.

[33]  P. Bosco,et al.  A High Percentage of Skin Melanoma Cells Expresses SPANX Proteins , 2009, The American Journal of dermatopathology.

[34]  A. Weeraratna,et al.  Sperm-Derived SPANX-B Is a Clinically Relevant Tumor Antigen That Is Expressed in Human Tumors and Readily Recognized by Human CD4+ and CD8+ T Cells , 2009, Clinical Cancer Research.

[35]  M. C. Cardoso,et al.  The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication , 2008, The Journal of cell biology.

[36]  Kaushik Sengupta,et al.  Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. , 2008, Genes & development.

[37]  E. Cabuy,et al.  Primary laminopathy fibroblasts display altered genome organization and apoptosis , 2007, Aging cell.

[38]  K. Honda,et al.  Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors , 2006 .

[39]  Ignacio Varela,et al.  Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation , 2005, Nature.

[40]  E. Koonin,et al.  The SPANX gene family of cancer/testis-specific antigens: rapid evolution and amplification in African great apes and hominids. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[41]  H. Frierson,et al.  Genomic Organization, Incidence, and Localization of the SPAN-X Family of Cancer-Testis Antigens in Melanoma Tumors and Cell Lines , 2004, Clinical Cancer Research.

[42]  U. Weidle,et al.  The human SPANX multigene family: genomic organization, alignment and expression in male germ cells and tumor cell lines. , 2003, Gene.

[43]  M. Chiriva-Internati,et al.  Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies. , 2003, Blood.

[44]  R. Goldman,et al.  Review: the dynamics of the nuclear lamins during the cell cycle-- relationship between structure and function. , 2000, Journal of structural biology.

[45]  U. Weidle,et al.  CTp11, a novel member of the family of human cancer/testis antigens. , 1999, Cancer research.

[46]  B. Williams,et al.  Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays , 1998 .

[47]  L. Gerace,et al.  Lamins A and C bind and assemble at the surface of mitotic chromosomes , 1990, The Journal of cell biology.

[48]  Samir Guglani.  Death , 1890, The Lancet.

[49]  M. Herlyn,et al.  Heterogeneity in Melanoma. , 2016, Cancer treatment and research.

[50]  B. Kennedy,et al.  RB and lamins in cell cycle regulation and aging. , 2014, Advances in experimental medicine and biology.

[51]  K. Honda,et al.  Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. , 2006, Immunity.

[52]  S. Coonrod,et al.  Differential Nuclear Localization of the Cancer/Testis-Associated Protein, SPAN-X/CTp11, in Transfected Cells and in 50% of Human Spermatozoa1 , 2001, Biology of reproduction.

[53]  B. Williams,et al.  Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[54]  G. Krohne,et al.  The nuclear lamins. A multigene family of proteins in evolution and differentiation. , 1986, Experimental cell research.