Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer
Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-08-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13255 |
| _version_ | 1828356763951300608 |
|---|---|
| author | Kavya Ganapathy Christopher Ngo Thomas Andl Domenico Coppola Jong Park Ratna Chakrabarti |
| author_facet | Kavya Ganapathy Christopher Ngo Thomas Andl Domenico Coppola Jong Park Ratna Chakrabarti |
| author_sort | Kavya Ganapathy |
| collection | DOAJ |
| description | Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR‐30e through the regulation of genes involved in various signaling pathways. We noted loss of miR‐30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR‐30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR‐30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR‐30e and its RNA targets. We noted a newly identified reciprocal relationship between miR‐30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR‐30e. Transcriptome profiling and quantitative real‐time PCR (qRT‐PCR) validation of miR‐30e‐expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR‐30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa. |
| first_indexed | 2024-04-14T03:04:09Z |
| format | Article |
| id | doaj.art-b3ea6c23bd05461588e3fe5f872252a4 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-14T03:04:09Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-b3ea6c23bd05461588e3fe5f872252a42022-12-22T02:15:49ZengWileyMolecular Oncology1574-78911878-02612022-08-0116162936295810.1002/1878-0261.13255Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancerKavya Ganapathy0Christopher Ngo1Thomas Andl2Domenico Coppola3Jong Park4Ratna Chakrabarti5Burnett School of Biomedical Sciences University of Central Florida Orlando Florida USABurnett School of Biomedical Sciences University of Central Florida Orlando Florida USABurnett School of Biomedical Sciences University of Central Florida Orlando Florida USADepartment of Pathology Moffitt Cancer Center Tampa Florida USADepartment of Cancer Epidemiology Moffitt Cancer Center Tampa Florida USABurnett School of Biomedical Sciences University of Central Florida Orlando Florida USAProstate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR‐30e through the regulation of genes involved in various signaling pathways. We noted loss of miR‐30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR‐30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR‐30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR‐30e and its RNA targets. We noted a newly identified reciprocal relationship between miR‐30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR‐30e. Transcriptome profiling and quantitative real‐time PCR (qRT‐PCR) validation of miR‐30e‐expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR‐30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa.https://doi.org/10.1002/1878-0261.13255apoptosiscell cycleHELLPARmicroRNAtranscriptomicsubiquitination |
| spellingShingle | Kavya Ganapathy Christopher Ngo Thomas Andl Domenico Coppola Jong Park Ratna Chakrabarti Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer Molecular Oncology apoptosis cell cycle HELLPAR microRNA transcriptomics ubiquitination |
| title | Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| title_full | Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| title_fullStr | Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| title_full_unstemmed | Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| title_short | Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| title_sort | anticancer function of microrna 30e is mediated by negative regulation of hellpar a noncoding macrorna and genes involved in ubiquitination and cell cycle progression in prostate cancer |
| topic | apoptosis cell cycle HELLPAR microRNA transcriptomics ubiquitination |
| url | https://doi.org/10.1002/1878-0261.13255 |
| work_keys_str_mv | AT kavyaganapathy anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer AT christopherngo anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer AT thomasandl anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer AT domenicocoppola anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer AT jongpark anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer AT ratnachakrabarti anticancerfunctionofmicrorna30eismediatedbynegativeregulationofhellparanoncodingmacrornaandgenesinvolvedinubiquitinationandcellcycleprogressioninprostatecancer |