Prolyl hydroxylase P4HA1 is amplified, overexpressed in prostate cancer and enhances cancer invasion by altering MMP1 expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Balabhadrapatruni Chakravarthi
PROVIDER: E-GEOD-55787 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Recent studies including next-generation sequencing have identified genomic events in prostate cancer including ETS gene fusions. However, it is critical to identify druggable targets for prostate cancer and their mechanism of action for therapeutic intervention. Here, we show that prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) is overexpressed in aggressive prostate cancer and amplified in a subset of metastatic prostate cancer. This study provides mechanistic insights of P4HA1 regulation and its mode of action including its role in regulating MMP1. Importantly, P4HA1 mediated invasion in cancer cells could be reversed using MMP1 inhibitor, revealing therapeutic utility of targeting P4HA1 either directly or by inhibiting its downstream effectors.
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Project description:The epidemiologic association between statin use and decreased risk of advanced prostate cancer suggests that statins may inhibit prostate cancer development and/or progression. Studies were performed to determine the effects of a model statin, atorvastatin (ATO), on the proliferation and differentiation of prostate cancer cells, and to identify possible mechanisms of ATO action. ATO inhibited the in vitro proliferation of both LNCaP and PC3 human prostate cancer cells in dose-dependent fashion. The greater inhibitory activity of ATO in PC3 cells was associated with induction of autophagy in that cell line, as demonstrated by increased expression of LC3-II. miR-182 was consistently upregulated by ATO in PC3 cells, but not in LNCaP cells. ATO upregulation of miR-182 in PC3 cells was p53-independent and was reversed by geranylgeraniol. Transfection of miR-182 inhibitors decreased expression of miR-182 by >98% and attenuated the antiproliferative activity of ATO. miR-182 expression in PC3 cells was also increased in response to stress induced by serum withdrawal, suggesting that miR-182 upregulation can occur due to nutritional stress. Bcl2 and p21 were identified to be potential target genes of miR-182 in PC3 cells. Bcl2 was downregulated and p21 was upregulated in PC3 cells exposed to ATO. These data suggest that miR-182 may be a stress-responsive miRNA that mediates ATO action in prostate cancer cells. Gene and miRNA expression in two prostate cancer cell lines treated with Atorvastatin vs. untreated control.
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Project description:Protein hydroxylation extensively regulates cellular signaling by affecting protein stability, protein-protein interaction and protein activity, and its dysregulation contributes to the pathogenesis of various diseases including cancers. However, because of the transient nature of the enzyme-substrate interaction, identifying new prolyl hydroxylation substrates remains a daunting challenge. Here, by developing a novel substrate-trapping strategy combining tumor hypoxia and hydroxylase pharmacological inhibition with TAP-TAG purification followed by mass spectrometry, we identify ADSL as a bona fide EglN2 prolyl hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is significantly higher in TNBC than in the other breast cancer subtypes and normal breast tissues. Functionally, ADSL knock out greatly impairs TNBC 2-D and 3-D cell proliferation and invasiveness in vitro, as well as TNBC tumorigenesis and metastasis in xenograft models. Mechanistically, the integrated transcriptome and metabolome analysis reveals that ADSL promotes the activation of the oncogene cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL hydroxylation. Specifically, ADSL, by affecting adenosine levels, controls the expression of the long non-coding RNA MIR22HG, which negatively regulates the oncogene cMYC protein level and, thus, cMYC target gene expression. Our findings identify ADSL and ADSL hydroxylation as potential therapeutic targets in TNBC.
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