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Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXR? expression and cholesterol homeostasis.

ABSTRACT: Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol accumulation. The regulation of these pathways is complex with transcriptional regulation by sterol-regulatory element-binding protein (SREBP) and liver X receptor/retinoid X receptor (RXR) transcription factors but poorly understood at the post-transcriptional levels. MiR-128-2 increases the expression of SREBP2 and decreases the expression of SREBP1 in HepG2, MCF7 and HEK293T cells independent of sirtuin 1 (SIRT1) status. MiR-128-2 inhibits the expression of ABCA1, ABCG1 and RXR? directly through a miR-128-2-binding site within their respective 3'untranslated regions. The administration of miR-128-2 leads to decline in the protein and mRNA levels of ABCA1, ABCG1 and RXR?. Conversely, anti-miRNA treatment leads to increased ABCA1, ABCG1 and RXR? expression. The inverse correlation between miR-128-2 and its targets viz. ABCA1 and ABCG1 was also established during high-fat diet in different mice tissues. Our data show that cholesterol efflux is attenuated by miR-128-2 overexpression and, conversely, stimulated by miR-128-2 silencing. Further, we also observed the induction of ER stress response by miR-128-2. In this study, we provide the first evidence of miR-128-2 to be a new regulator of cholesterol homeostasis. Our study shows dual role of miR-128-2, as a pro-apoptotic molecule as well as a regulator of cholesterol homeostasis.

SUBMITTER: Adlakha YK

PROVIDER: S-EPMC3763462 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRα expression and cholesterol homeostasis.

Adlakha Y K YK Khanna S S Singh R R Singh V P VP Agrawal A A Saini N N

Cell death & disease 20130829

Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol ...[more]

PMID: 23990020

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Project description:BackgroundActivation of p53-mediated gene transcription is a critical cellular response to DNA damage and involves a phosphorylation-acetylation cascade of p53. The discovery of differences in the response to different agents raises the question whether some of the p53 oncosuppressor functions might be exerted by different posttranslational modifications. Stress-induced homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates p53 at serine-46 (Ser46) for p53 apoptotic activity; p53 acetylation at different C-terminus lysines including p300-mediated lysine-382 (Lys382) is also required for full activation of p53 transcriptional activity. The purpose of the current study was to evaluate the interplay among HIPK2, p300, and p53 in p53 acetylation and apoptotic transcriptional activity in response to drug by using siRNA interference, p300 overexpression or deacetylase inhibitors, in cancer cells.ResultsKnockdown of HIPK2 inhibited both adriamycin-induced Ser46 phosphorylation and Lys382 acetylation in p53 protein; however, while combination of ADR and zinc restored Ser46 phosphorylation it did not recover Lys382 acetylation. Chromatin immunoprecipitation studies showed that HIPK2 was required in vivo for efficient p300/p53 co-recruitment onto apoptotic promoters and that both p53 modifications at Ser46 and Lys382 were necessary for p53 apoptotic transcription. Thus, p53Lys382 acetylation in HIPK2 knockdown as well as p53 apoptotic activity in response to drug could be rescued by p300 overexpression. Similar effect was obtained with the Sirt1-inhibitor nicotinamide. Interestingly trichostatin A (TSA), the inhibitor of histone deacetylase complexes (HDAC) did not have effect, suggesting that Sirt1 was the deacetylase involved in p53 deacetylation in HIPK2 knockdown.ConclusionThese results reveal a novel role for HIPK2 in activating p53 apoptotic transcription. Our results indicate that HIPK2 may regulate the balance between p53 acetylation and deacetylation, by stimulating on one hand co-recruitment of p300 and p53Lys382 on apoptotic promoters and on the other hand by inhibiting Sirt1 deacetylase activity. We attempted to reactivate p53 apoptotic transcriptional activity by rescuing both Ser46 and Lys382 modification in response to drug. Our data propose combination strategies for the treatment of tumors with dysfunctional p53 and/or HIPK2 that include classical chemotherapy with pharmacological or natural agents such as Sirt1-deacetylase inhibitors or zinc, respectively.

Dataset Information

Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXR? expression and cholesterol homeostasis.

Publications

Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRα expression and cholesterol homeostasis.

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