Relationship between metabolic function and onset of cancer identified
Molecular mechanism links metabolic process and cancer metastasis
Genome projects have clarified that cancer is a disease caused by damage to genes. Recently, close examination of genes have unveiled that cancer does not develop in a short period of time, but that its occurrence and development have many factors: external factors (such as smoking and drinking) and inflammation (infection) intertwine and damaged genes accumulate over many years, leading to malignant cancer.
In developed countries including Japan, lifestyle-related diseases such as diabetes are also a great challenge. Cancer and lifestyle-related diseases have a similarity in that metabolism involving the breakdown of sugar plays an important role; however, only in cancer, are genes damaged and to what degree metabolism is related to cancer and how such a relationship is related to the degree of malignancy in cancer have been unknown.
A group of researchers at Osaka University have clarified a molecular mechanism linking a metabolic process to cancer metastasis.
• ISHII Hideshi , Specially Appointed Professor, Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University
• MORI Masaki , Professor, Division of Gastroenterological Surgery, Division of Surgical Medicine, Graduate School of Medicine, Osaka University
The mechanism clarified by this group was that, unexpectedly, proteins related to metabolism left their positions and controlled the occurrence of cancer metastasis. This unique molecular mechanism will contribute to enabling a diagnosis with a high degree of accuracy and treatment of targeting a refractory digestive system cancer with metastasis. Elucidating this common molecular mechanism will lead to the clarification of the nature of such pathological conditions and will be helpful in achieving more precise diagnosis and effective treatment.
Abstract
Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial–mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β–induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.
To learn more about this research, please view the full research report entitled " Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition " at this page of the Proceedings of the National Academy of Sciences website.
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