KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer

Xiaozhong Xiong, Markus Schober, Evelyne Tassone, Alireza Khodadadi-Jamayran, Ana Sastre-Perona, Hua Zhou, Aristotelis Tsirigos, Steven Shen, Miao Chang, Jonathan Melamed, Liliana Ossowski, Elaine L. Wilson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer. Available criteria for segregating prostate cancer patients into those requiring therapeutic intervention and those who can be followed are inadequate. Xiong et al. show that KLF4 and its downstream targets make up a gene signature that identifies indolent tumors. This approach may improve prognosis and identify therapeutic targets for advanced cancer.

Original languageEnglish (US)
Pages (from-to)3006-3020.e7
JournalCell reports
Volume25
Issue number11
DOIs
StatePublished - Dec 11 2018

Bibliographical note

Funding Information:
We thank Dr. O. Witte (UCLA) for the Akt constructs, Dr. D. Fenyo (NYU School of Medicine) for help with the Monte Carlo simulations, and Susan Logan (NYU School of Medicine) and Michael Garabedian (NYU School of Medicine) for helpful discussions. This research was supported by the NIH, United States (R01CA132641 to E.L.W.; R01CA181111 to M.S.; T32CA16002 to M.C.; and T32CA009161 and T32AR064184 to A.S.-P.), and the American Cancer Society, United States (RSG-16-033-01-DDC to M.S.). This research was also supported by the Department of Urology and the Kimmel Center for Stem Cell Biology. We thank the Perlmutter Cancer Center (P30CA016087) for partial support of core funding (Applied Bioinformatics Laboratories, Genome Technology Center, Experimental Pathology Research Laboratory, and Cytometry and Cell Sorting Laboratory).

Funding Information:
We thank Dr. O. Witte (UCLA) for the Akt constructs, Dr. D. Fenyo (NYU School of Medicine) for help with the Monte Carlo simulations, and Susan Logan (NYU School of Medicine) and Michael Garabedian (NYU School of Medicine) for helpful discussions. This research was supported by the NIH , United States ( R01CA132641 to E.L.W.; R01CA181111 to M.S.; T32CA16002 to M.C.; and T32CA009161 and T32AR064184 to A.S.-P.), and the American Cancer Society , United States ( RSG-16-033-01-DDC to M.S.). This research was also supported by the Department of Urology and the Kimmel Center for Stem Cell Biology. We thank the Perlmutter Cancer Center ( P30CA016087 ) for partial support of core funding (Applied Bioinformatics Laboratories, Genome Technology Center, Experimental Pathology Research Laboratory, and Cytometry and Cell Sorting Laboratory).

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • EMT
  • Klf4
  • adult prostate stem cells
  • gene signature
  • malignant transformation
  • prognosis
  • prostate cancer
  • stem cell homeostasis

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