title: The miR-124-prolyl hydroxylase P4HA1-MMP1 axis plays a critical role in prostate cancer progression.
abstract: Collagen prolyl hydroxylases (C-P4HAs) are a family of enzymes involved in collagen biogenesis. One of the isoforms of P4HA, Prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), catalyzes the formation of 4-hydroxyproline that is essential for the proper three-dimensional folding of newly synthesized procollagen chains. Here, we show the overexpression of P4HA1 in aggressive prostate cancer. Immunohistochemical analysis using tissue microarray demonstrated that P4HA1 expression was correlated with prostate cancer progression. Using in vitro studies, we showed that P4HA1 plays a critical role in prostate cancer cell growth and tumor progression. Expression profiling studies using P4HA1 modulated prostate cells suggested regulation of Matrix metalloproteases 1. The invasive properties of P4HA1 overexpressing cells were reversed by blocking MMP1. Our studies indicate P4HA1 copy number gain in a subset of metastatic prostate tumors and its expression is also regulated by microRNA-124. MiR-124 in turn is negatively regulated by transcriptional repressors EZH2 and CtBP1, both of which are overexpressed in aggressive prostate cancer. Chick chorioallantoic membrane (CAM) assay and mice xenograft investigations show that P4HA1 is required for tumor growth and metastasis in vivo. Our observations suggest that P4HA1 plays a critical role in prostate cancer progression and could serve as a viable therapeutic target.
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Balabhadrapatruni V S K
authors.initials: BV
authors.lastname: Chakravarthi
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan; These authors contributted equally to this work.
authors.forename: Satya Sreehari
authors.initials: SS
authors.lastname: Pathi
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan; These authors contributted equally to this work.
authors.forename: Moloy T
authors.initials: MT
authors.lastname: Goswami
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieślik
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan.
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Nallasivam
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan; Present Address: Department of Hematology and Oncology, Providence Hospital and Medical Center, Southfiled, MI 48075, USA.
authors.forename: Subramanyeswara R
authors.initials: SR
authors.lastname: Arekapudi
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Jing
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Athanikar
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Carskadon
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan; Department of Urology, University of Michigan; Howard Hughes Medical Institute, University of Michigan Medical School; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Michigan Center for Translational Pathology; Department of Pathology, University of Michigan; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D015870:Gene Expression; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: C404492:FLRT3 protein, human; C509207:MIRN124 microRNA, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; C510863:P4HA1 protein, human; D011393:Procollagen-Proline Dioxygenase; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1