An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer

Xin Lu, Xiaolu Pan, Chang Jiun Wu, Di Zhao, Shan Feng, Yong Zang, Rumi Lee, Sunada Khadka, Samirkumar B. Amin, Eun Jung Jin, Xiaoying Shang, Pingna Deng, Yanting Luo, William R. Morgenlander, Jacqueline Weinrich, Xuemin Lu, Shan Jiang, Qing Chang, Nora M. Navone, Patricia TroncosoRonald A. DePinho, Y. Alan Wang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/b-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer. Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis.

Original languageEnglish (US)
Pages (from-to)3823-3833
Number of pages11
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - Jul 15 2018
Externally publishedYes

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Prostatic Neoplasms
Oncogenes
Neoplasm Metastasis
Biomarkers
Lymph Nodes
Catenins
Neoplasms
Chromosomal Instability
Neoplasm Grading
Genomics
Heterografts
Transcriptional Activation
Fingers
Carcinogenesis
Up-Regulation
Ligands
Bone and Bones
Growth
Genes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer. / Lu, Xin; Pan, Xiaolu; Wu, Chang Jiun; Zhao, Di; Feng, Shan; Zang, Yong; Lee, Rumi; Khadka, Sunada; Amin, Samirkumar B.; Jin, Eun Jung; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Morgenlander, William R.; Weinrich, Jacqueline; Lu, Xuemin; Jiang, Shan; Chang, Qing; Navone, Nora M.; Troncoso, Patricia; DePinho, Ronald A.; Wang, Y. Alan.

In: Cancer Research, Vol. 78, No. 14, 15.07.2018, p. 3823-3833.

Research output: Contribution to journalArticle

Lu, X, Pan, X, Wu, CJ, Zhao, D, Feng, S, Zang, Y, Lee, R, Khadka, S, Amin, SB, Jin, EJ, Shang, X, Deng, P, Luo, Y, Morgenlander, WR, Weinrich, J, Lu, X, Jiang, S, Chang, Q, Navone, NM, Troncoso, P, DePinho, RA & Wang, YA 2018, 'An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer', Cancer Research, vol. 78, no. 14, pp. 3823-3833. https://doi.org/10.1158/0008-5472.CAN-17-3564
Lu, Xin ; Pan, Xiaolu ; Wu, Chang Jiun ; Zhao, Di ; Feng, Shan ; Zang, Yong ; Lee, Rumi ; Khadka, Sunada ; Amin, Samirkumar B. ; Jin, Eun Jung ; Shang, Xiaoying ; Deng, Pingna ; Luo, Yanting ; Morgenlander, William R. ; Weinrich, Jacqueline ; Lu, Xuemin ; Jiang, Shan ; Chang, Qing ; Navone, Nora M. ; Troncoso, Patricia ; DePinho, Ronald A. ; Wang, Y. Alan. / An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer. In: Cancer Research. 2018 ; Vol. 78, No. 14. pp. 3823-3833.
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abstract = "Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/b-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer. Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis.",
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AU - Lu, Xin

AU - Pan, Xiaolu

AU - Wu, Chang Jiun

AU - Zhao, Di

AU - Feng, Shan

AU - Zang, Yong

AU - Lee, Rumi

AU - Khadka, Sunada

AU - Amin, Samirkumar B.

AU - Jin, Eun Jung

AU - Shang, Xiaoying

AU - Deng, Pingna

AU - Luo, Yanting

AU - Morgenlander, William R.

AU - Weinrich, Jacqueline

AU - Lu, Xuemin

AU - Jiang, Shan

AU - Chang, Qing

AU - Navone, Nora M.

AU - Troncoso, Patricia

AU - DePinho, Ronald A.

AU - Wang, Y. Alan

PY - 2018/7/15

Y1 - 2018/7/15

N2 - Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/b-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer. Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis.

AB - Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/b-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer. Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis.

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