Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis.
The mechanisms by which Myc overexpression or Pten loss promotes prostate cancer development are poorly understood. We identified the chromatin remodeling protein, ING4, as a crucial switch downstream of Myc and Pten that is required for human prostate epithelial differentiation. Myc-induced transient expression of ING4 is required for the differentiation of basal epithelial cells into luminal cells, while sustained ING4 expression induces apoptosis. ING4 expression is lost in >60% of human primary prostate tumors. ING4 or Pten loss prevents epithelial cell differentiation, which was necessary for tumorigenesis. Pten loss prevents differentiation by blocking ING4 expression, which is rescued by ING4 re-expression. Pten or ING4 loss generates tumor cells that co-express basal and luminal markers, indicating prostate oncogenesis occurs through disruption of an intermediate step in the prostate epithelial differentiation program. Thus, we identified a new epithelial cell differentiation switch involving Myc, Pten, and ING4, which when disrupted leads to prostate tumorigenesis. Myc overexpression and Pten loss are common genetic abnormalities in prostate cancer, whereas loss of the tumor suppressor ING4 has not been reported. This is the first demonstration that transient ING4 expression is absolutely required for epithelial differentiation, its expression is dependent on Myc and Pten, and it is lost in the majority of human prostate cancers. This is the first demonstration that loss of ING4, either directly or indirectly through loss of Pten, promotes Myc-driven oncogenesis by deregulating differentiation. The clinical implication is that Pten/ING4 negative and ING4-only negative tumors may reflect two distinct subtypes of prostate cancer.
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Penny L
PL
Berger
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, ArizonaAuthors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Sander B
SB
Frank
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Veronique V
VV
Schulz
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, ArizonaAuthors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Eric A
EA
Nollet
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Mathew J
MJ
Edick
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Brittany
B
Holly
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Ting-Tung A
TT
Chang
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Galen
G
Hostetter
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona.
Suwon
S
Kim
Authors' Affiliations: Laboratory of Integrin Signaling; Laboratory of Translational Imaging; and Laboratory of Analytical Pathology; and Van Andel Institute Graduate School, Grand Rapids; Genetics Graduate Program, Michigan State University, Lansing, Michigan; and Tranlational Genomics Research Institute and University of Arizona College of Medicine, Phoenix, Arizona cindy.miranti@vai.org.
Cindy K
CK
Miranti
D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
C090121:BNIP3 protein, human; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; C489427:MYC protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human