An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer

An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer. Lu, X., Pan, X., Wu, C., Zhao, D., Feng, S., Zang, Y., Lee, R., Khadka, S., Amin, S. B, Jin, E., Shang, X., Deng, P., Luo, Y., Morgenlander, W. R, Weinrich, J., Lu, X., Jiang, S., Chang, Q., Navone, N. M, Troncoso, P., DePinho, R. A, & Wang, Y A. Cancer Res., 78(14):3823-3833, July, 2018.

Paper doi abstract bibtex

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/$β$-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. Cancer Res; 78(14); 3823-33. ©2018 AACR.

@ARTICLE{Lu2018-rm,
  title    = "An In Vivo Screen Identifies {PYGO2} as a Driver for Metastatic
              Prostate Cancer",
  author   = "Lu, Xin and Pan, Xiaolu and Wu, Chang-Jiun and Zhao, Di and Feng,
              Shan and Zang, Yong and Lee, Rumi and Khadka, Sunada and Amin,
              Samirkumar B and Jin, Eun-Jung and Shang, Xiaoying and Deng,
              Pingna and Luo, Yanting and Morgenlander, William R and Weinrich,
              Jacqueline and Lu, Xuemin and Jiang, Shan and Chang, Qing and
              Navone, Nora M and Troncoso, Patricia and DePinho, Ronald A and
              Wang, Y Alan",
  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/$\beta$-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. Cancer Res;
              78(14); 3823-33. \copyright{}2018 AACR.",
  journal  = "Cancer Res.",
  volume   =  78,
  number   =  14,
  pages    = "3823-3833",
  month    =  jul,
  year     =  2018,
  url      = "http://dx.doi.org/10.1158/0008-5472.CAN-17-3564",
  language = "en",
  issn     = "0008-5472, 1538-7445",
  pmid     = "29769196",
  doi      = "10.1158/0008-5472.CAN-17-3564",
  authorclass = {coauthor},
  contribution = {data\_analysis},
  affiliation = {BCM, MDANDERSON}
}

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