Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation

Nagarathinam Selvaraj, Justin A. Budka, Mary W. Ferris, Travis Jerde, Peter Hollenhorst

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. Often, RAS/ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K/AKT is activated by loss of the tumor suppressor PTEN. In prostate cancer, PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. We have previously shown that over-expression of " oncogenic" ETS transcription factors, which occurs in about one-half of prostate tumors due to chromosome rearrangement, can bypass the need for RAS/ERK signaling in the activation of a cell migration gene expression program. In this study we test the role of RAS/ERK and PI3K/AKT signaling in the function of oncogenic ETS proteins.Results: We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1.Conclusions: Our findings indicate that oncogenic ETS rearrangements cause a cell migration gene expression program to switch from RAS/ERK control to PI3K/AKT control and provide a possible explanation for the high frequency of PTEN, but not RAS/RAF mutations in prostate cancer.

Original languageEnglish
Article number61
JournalMolecular Cancer
Volume13
Issue number1
DOIs
StatePublished - Mar 19 2014

Fingerprint

Phosphatidylinositol 3-Kinases
Cell Movement
Prostatic Neoplasms
Gene Expression
Mutation
Prostate
Neoplasms
Transcription Factors
Proteins
Transcription Factor AP-1
Oncogenes
Chromosomes
Carcinoma

Keywords

  • Cell migration
  • ETS
  • PI3K/AKT
  • Prostate cancer
  • RAS/ERK

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation. / Selvaraj, Nagarathinam; Budka, Justin A.; Ferris, Mary W.; Jerde, Travis; Hollenhorst, Peter.

In: Molecular Cancer, Vol. 13, No. 1, 61, 19.03.2014.

Research output: Contribution to journalArticle

@article{a2e4e93f0582475996b0041f9cae9c0e,
title = "Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation",
abstract = "Background: The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. Often, RAS/ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K/AKT is activated by loss of the tumor suppressor PTEN. In prostate cancer, PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. We have previously shown that over-expression of {"} oncogenic{"} ETS transcription factors, which occurs in about one-half of prostate tumors due to chromosome rearrangement, can bypass the need for RAS/ERK signaling in the activation of a cell migration gene expression program. In this study we test the role of RAS/ERK and PI3K/AKT signaling in the function of oncogenic ETS proteins.Results: We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1.Conclusions: Our findings indicate that oncogenic ETS rearrangements cause a cell migration gene expression program to switch from RAS/ERK control to PI3K/AKT control and provide a possible explanation for the high frequency of PTEN, but not RAS/RAF mutations in prostate cancer.",
keywords = "Cell migration, ETS, PI3K/AKT, Prostate cancer, RAS/ERK",
author = "Nagarathinam Selvaraj and Budka, {Justin A.} and Ferris, {Mary W.} and Travis Jerde and Peter Hollenhorst",
year = "2014",
month = "3",
day = "19",
doi = "10.1186/1476-4598-13-61",
language = "English",
volume = "13",
journal = "Molecular Cancer",
issn = "1476-4598",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation

AU - Selvaraj, Nagarathinam

AU - Budka, Justin A.

AU - Ferris, Mary W.

AU - Jerde, Travis

AU - Hollenhorst, Peter

PY - 2014/3/19

Y1 - 2014/3/19

N2 - Background: The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. Often, RAS/ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K/AKT is activated by loss of the tumor suppressor PTEN. In prostate cancer, PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. We have previously shown that over-expression of " oncogenic" ETS transcription factors, which occurs in about one-half of prostate tumors due to chromosome rearrangement, can bypass the need for RAS/ERK signaling in the activation of a cell migration gene expression program. In this study we test the role of RAS/ERK and PI3K/AKT signaling in the function of oncogenic ETS proteins.Results: We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1.Conclusions: Our findings indicate that oncogenic ETS rearrangements cause a cell migration gene expression program to switch from RAS/ERK control to PI3K/AKT control and provide a possible explanation for the high frequency of PTEN, but not RAS/RAF mutations in prostate cancer.

AB - Background: The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. Often, RAS/ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K/AKT is activated by loss of the tumor suppressor PTEN. In prostate cancer, PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. We have previously shown that over-expression of " oncogenic" ETS transcription factors, which occurs in about one-half of prostate tumors due to chromosome rearrangement, can bypass the need for RAS/ERK signaling in the activation of a cell migration gene expression program. In this study we test the role of RAS/ERK and PI3K/AKT signaling in the function of oncogenic ETS proteins.Results: We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1.Conclusions: Our findings indicate that oncogenic ETS rearrangements cause a cell migration gene expression program to switch from RAS/ERK control to PI3K/AKT control and provide a possible explanation for the high frequency of PTEN, but not RAS/RAF mutations in prostate cancer.

KW - Cell migration

KW - ETS

KW - PI3K/AKT

KW - Prostate cancer

KW - RAS/ERK

UR - http://www.scopus.com/inward/record.url?scp=84899554631&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899554631&partnerID=8YFLogxK

U2 - 10.1186/1476-4598-13-61

DO - 10.1186/1476-4598-13-61

M3 - Article

C2 - 24642271

AN - SCOPUS:84899554631

VL - 13

JO - Molecular Cancer

JF - Molecular Cancer

SN - 1476-4598

IS - 1

M1 - 61

ER -