MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer
Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-r...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/12/2902 |
| _version_ | 1797489211082801152 |
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| author | Sara De Martino Egidio Iorio Chiara Cencioni Aurora Aiello Francesco Spallotta Mattea Chirico Maria Elena Pisanu Claudio Grassi Alfredo Pontecorvi Carlo Gaetano Simona Nanni Antonella Farsetti |
| author_facet | Sara De Martino Egidio Iorio Chiara Cencioni Aurora Aiello Francesco Spallotta Mattea Chirico Maria Elena Pisanu Claudio Grassi Alfredo Pontecorvi Carlo Gaetano Simona Nanni Antonella Farsetti |
| author_sort | Sara De Martino |
| collection | DOAJ |
| description | Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. Results. In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. Conclusions. These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective. |
| first_indexed | 2024-03-10T00:13:14Z |
| format | Article |
| id | doaj.art-9a54ffd1d36c47e6b21981d47b772653 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:13:14Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9a54ffd1d36c47e6b21981d47b7726532023-11-23T15:56:08ZengMDPI AGCancers2072-66942022-06-011412290210.3390/cancers14122902MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate CancerSara De Martino0Egidio Iorio1Chiara Cencioni2Aurora Aiello3Francesco Spallotta4Mattea Chirico5Maria Elena Pisanu6Claudio Grassi7Alfredo Pontecorvi8Carlo Gaetano9Simona Nanni10Antonella Farsetti11Department of Translational Medicine and Surgery, Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyIstituto Superiore di Sanità, 00161 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyIstituto Superiore di Sanità, 00161 Rome, ItalyIstituto Superiore di Sanità, 00161 Rome, ItalyFondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyFondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyIstituti Clinici Scientifici Maugeri, 27100 Pavia, ItalyFondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyNational Research Council (CNR)-IASI, 00185 Rome, ItalyBackground. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. Results. In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. Conclusions. These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective.https://www.mdpi.com/2072-6694/14/12/2902choline kinase Aprostate cancerMALAT1metabolic rewiringphospholipid metabolism |
| spellingShingle | Sara De Martino Egidio Iorio Chiara Cencioni Aurora Aiello Francesco Spallotta Mattea Chirico Maria Elena Pisanu Claudio Grassi Alfredo Pontecorvi Carlo Gaetano Simona Nanni Antonella Farsetti MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer Cancers choline kinase A prostate cancer MALAT1 metabolic rewiring phospholipid metabolism |
| title | MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer |
| title_full | MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer |
| title_fullStr | MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer |
| title_full_unstemmed | MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer |
| title_short | MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer |
| title_sort | malat1 as a regulator of the androgen dependent choline kinase a gene in the metabolic rewiring of prostate cancer |
| topic | choline kinase A prostate cancer MALAT1 metabolic rewiring phospholipid metabolism |
| url | https://www.mdpi.com/2072-6694/14/12/2902 |
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