Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis

Penny L. Berger, Sander B. Frank, Veronique V. Schulz, Eric A. Nollet, Mathew J. Edick, Brittany Holly, Ting Tung A Chang, Galen Hostetter, Suwon Kim, Cindy K. Miranti

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3357-3368
Number of pages12
JournalCancer Research
Volume74
Issue number12
DOIs
StatePublished - Jun 15 2014

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Prostate
Cell Differentiation
Carcinogenesis
Epithelial Cells
Prostatic Neoplasms
Neoplasms
Chromatin Assembly and Disassembly
Apoptosis
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Berger, P. L., Frank, S. B., Schulz, V. V., Nollet, E. A., Edick, M. J., Holly, B., ... Miranti, C. K. (2014). Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. Cancer Research, 74(12), 3357-3368. https://doi.org/10.1158/0008-5472.CAN-13-3076

Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. / Berger, Penny L.; Frank, Sander B.; Schulz, Veronique V.; Nollet, Eric A.; Edick, Mathew J.; Holly, Brittany; Chang, Ting Tung A; Hostetter, Galen; Kim, Suwon; Miranti, Cindy K.

In: Cancer Research, Vol. 74, No. 12, 15.06.2014, p. 3357-3368.

Research output: Contribution to journalArticle

Berger, PL, Frank, SB, Schulz, VV, Nollet, EA, Edick, MJ, Holly, B, Chang, TTA, Hostetter, G, Kim, S & Miranti, CK 2014, 'Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis', Cancer Research, vol. 74, no. 12, pp. 3357-3368. https://doi.org/10.1158/0008-5472.CAN-13-3076
Berger, Penny L. ; Frank, Sander B. ; Schulz, Veronique V. ; Nollet, Eric A. ; Edick, Mathew J. ; Holly, Brittany ; Chang, Ting Tung A ; Hostetter, Galen ; Kim, Suwon ; Miranti, Cindy K. / Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. In: Cancer Research. 2014 ; Vol. 74, No. 12. pp. 3357-3368.
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