title: Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.
abstract: The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Akash K
authors.initials: AK
authors.lastname: Kaushik
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shojaie
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Panzitt
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Rajni
authors.initials: R
authors.lastname: Sonavane
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Harene
authors.initials: H
authors.lastname: Venghatakrishnan
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Manikkam
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaslavsky
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Vasanta
authors.initials: V
authors.lastname: Putluri
authors.affiliation: Department of Zoology, Maharaja Sayajirao University of Baroda, Vadodara 390002, India.
authors.forename: Vihas T
authors.initials: VT
authors.lastname: Vasu
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Ayesha S
authors.initials: AS
authors.lastname: Khan
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Lloyd
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Szafran
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Subhamoy
authors.identifier: 0000-0001-7167-908X
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bader
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hangwen
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Pathology University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Efrosini
authors.initials: E
authors.lastname: Tsouko
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.|Genomic Medicine Program, Houston Methodist Research Institute, Houston, Texas 77030, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Benny A
authors.initials: BA
authors.lastname: Kaipparettu
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: McGuire
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Pathology University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Pathology University of Michigan, Ann Arbor, Michigan 48109, USA.|Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Palapattu
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: George
authors.initials: G
authors.lastname: Michailidis
authors.affiliation: Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006595:Hexosamines; C116385:MLXIPL protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt