SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors.
Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers.
1] Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA [2] Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA.
Shivani
S
Malik
1] Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA [2] Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA [3] Department of Experimental Medicine, Sapienza University, Rome, Italy.
Lidia
L
Villanova
Venture Science Laboratories, Daiichi Sankyo Co. Ltd., 1-2-58 Hiromachi, Tokyo 140-8710, Japan.
Shinji
S
Tanaka
Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Tokyo 134-8630.
Misato
M
Aonuma
Diabetes Center, University of California, San Francisco, San Francisco, California 94143.
Nilotpal
N
Roy
1] Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA [2] Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA.
Elisabeth
E
Berber
Department of Pathology, Stanford University, Stanford, California 94305, USA.
Jonathan R
JR
Pollack
Venture Science Laboratories, Daiichi Sankyo Co. Ltd., 1-2-58 Hiromachi, Tokyo 140-8710, Japan.
Eriko
E
Michishita-Kioi
1] Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA [2] Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA.
Katrin F
KF
Chua
D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D037761:Sirtuins / Q000235:genetics*
D002843:Chromatin; C510661:SIRT7 protein, human; D037761:Sirtuins