Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer
by
, and
Manqi Zhang
1,
Yasemin Ceyhan
2,
Shenglin Mei
3,4,
Taghreed Hirz
3,4,
David B. Sykes
3,4 and
Irina U. Agoulnik
5,6,7,* 1
Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC 27708, USA
2
Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
3
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
4
Harvard Stem Cell Institute, Cambridge, MA 02138, USA
5
Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
6
Biomolecular Science Institute, Florida International University, Miami, FL 33199, USA
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(22), 5418; https://doi.org/10.3390/cancers15225418
Submission received: 24 October 2023
/
Accepted: 4 November 2023
/
Published: 15 November 2023
(This article belongs to the Special Issue Actual Aspects of Prostate Cancer Treatment—An Interdisciplinary Approach (Volume II))
Simple Summary
Prostate cancer is a heterogeneous disease driven by multiple genetic alterations: the deletion or downregulation of tumor suppressors and the activation or amplification of oncogenes. Among the most frequently deleted tumor suppressors in prostate cancer are INPP4B and PTEN. We show that the loss of these proteins triggers distinct compensatory mechanisms that must be overcome for the progression from indolent to advanced stages of prostate cancer.
Abstract
The phosphatases INPP4B and PTEN are tumor suppressors that are lost in nearly half of advanced metastatic cancers. The loss of PTEN in prostate epithelium initially leads to an upregulation of several tumor suppressors that slow the progression of prostate cancer in mouse models. We tested whether the loss of INPP4B elicits a similar compensatory response in prostate tissue and whether this response is distinct from the one caused by the loss of PTEN. Knockdown of INPP4B but not PTEN in human prostate cancer cell lines caused a decrease in EZH2 expression. In Inpp4b−/− mouse prostate epithelium, EZH2 levels were decreased, as were methylation levels of histone H3. In contrast, Ezh2 levels were increased in the prostates of Pten−/− male mice. Contrary to PTEN, there was a positive correlation between INPP4B and EZH2 expression in normal human prostates and early-stage prostate tumors. Analysis of single-cell transcriptomic data demonstrated that a subset of EZH2-positive cells expresses INPP4B or PTEN, but rarely both, consistent with their opposing correlation with EZH2 expression. Unlike PTEN, INPP4B did not affect the levels of SMAD4 protein expression or Pml mRNA expression. Like PTEN, p53 protein expression and phosphorylation of Akt in Inpp4b−/− murine prostates were elevated. Taken together, the loss of INPP4B in the prostate leads to overlapping and distinct changes in tumor suppressor and oncogenic downstream signaling.
Keywords:
INPP4B; PTEN; EZH2; prostate cancer
