title: Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression.
abstract: AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.|b Department of Experimental Therapeutics , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Blessing
authors.affiliation: c Department of Molecular and Cellular Biology , Baylor College of Medicine , Houston , TX , USA.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: d Department of Clinical Cancer Prevention , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Reddy Bollu
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: White
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Pham
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Chenchu
authors.initials: C
authors.lastname: Lin
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Jonsson
authors.affiliation: e Departments of Cellular and Molecular Medicine , Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California , San Diego, La Jolla , CA , USA.
authors.forename: Constanza J
authors.initials: CJ
authors.lastname: Cortes
authors.affiliation: f Faculty of Health Sciences, University of Macau , Taipa , Macau , China.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
authors.affiliation: e Departments of Cellular and Molecular Medicine , Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California , San Diego, La Jolla , CA , USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.affiliation: b Department of Experimental Therapeutics , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: g Department of Engineering Technology , University of Houston , Houston , TX , USA.
authors.forename: Fatima A
authors.initials: FA
authors.lastname: Merchant
authors.affiliation: c Department of Molecular and Cellular Biology , Baylor College of Medicine , Houston , TX , USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: a Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.|h Genomic Medicine Program, The Houston Methodist Research Institute , Houston , TX , USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
mesh_terms: D000728:Androgens / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics*; D008297:Male; D009362:Neoplasm Metastasis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000728:Androgens; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D011944:Receptors, Androgen; C064972:TFEB protein, human
keywords: ATG4B; ATG4D; TFEB; ULK1; ULK2; androgen; androgen receptor (AR); autophagy; nuclear receptor; prostate cancer