The control of tissue architecture over nuclear organization is crucial for epithelial cell fate.
The remodeling of nuclear organization during differentiation and the dramatic alteration of nuclear organization associated with cancer development are well documented. However, the importance of tissue architecture in the control of nuclear organization remains to be determined. Differentiation of mammary epithelial cells into functional tissue structures, in three-dimensional culture, is characterized by a specific tissue architecture (i.e. a basoapical polarity axis), cell cycle exit and maintenance of cell survival. Here we show that induction of partial differentiation (i.e. basal polarity only, cell cycle exit and cell survival) by epigenetic mechanisms in malignant breast cells is sufficient to restore features of differentiation-specific nuclear organization, including perinucleolar heterochromatin, large splicing factor speckles, and distinct nuclear mitotic apparatus protein (NuMA) foci. Upon alteration of nuclear organization using an antibody against NuMA, differentiated non-neoplastic cells undergo apoptosis, whereas partially differentiated malignant cells enter the cell cycle. Non-neoplastic cells cultured under conditions that prevent the establishment of apical polarity also enter the cell cycle upon NuMA antibody treatment. These findings demonstrate that the differentiation status rather than the non-neoplastic or neoplastic origin of cells controls nuclear organization and suggest a link between nuclear organization and epigenetic mechanisms dictated by tissue architecture for the control of cell behavior.
Chandramouly
Gurushankar
G
Department of Basic Medical Sciences and Cancer Center, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026, USA.
Abad
Patricia C
PC
Knowles
David W
DW
Lelièvre
Sophie A
SA
D000951:Antigens, Neoplasm / Q000032:analysis; D034961:Antigens, Nuclear / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016764:Cell Polarity / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D024141:Collagen Type IV / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006657:Histones / Q000032:analysis; D006801:Humans; D039503:Integrin alpha6 / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D009025:Morpholines / Q000494:pharmacology; D018396:Mucin-1; D009077:Mucins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D034521:Nuclear Matrix-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D000071156:Promyelocytic Leukemia Protein; D011799:Quinazolines; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D020032:Tyrphostins / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin / Q000032:analysis
D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002867:Chromones; D024141:Collagen Type IV; D004791:Enzyme Inhibitors; D006657:Histones; D039503:Integrin alpha6; D019394:Ki-67 Antigen; C060192:MUC1 protein, human; D008565:Membrane Proteins; D009025:Morpholines; D018396:Mucin-1; D009077:Mucins; C050045:NUMA1 protein, human; D009363:Neoplasm Proteins; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000071156:Promyelocytic Leukemia Protein; D011799:Quinazolines; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020032:Tyrphostins; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; C070576:PML protein, human; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C512478:EGFR protein, human; D066246:ErbB Receptors