miR-449a Repression Leads to Enhanced NOTCH Signaling in TMPRSS2:ERG Fusion Positive Prostate Cancer Cells

Abstract

About 50% of prostate cancer (PCa) tumors are TMPRSS2:ERG (T2E) fusion-positive (T2E+), but the role of T2E in PCa progression is not fully understood. We were interested in investigating epigenomic alterations associated with T2E+ PCa. Using different sequencing cohorts, we found several transcripts of the miR-449 cluster to be repressed in T2E+ PCa. This repression correlated strongly with enhanced expression of NOTCH and several of its target genes in TCGA and ICGC PCa RNA-seq data. We corroborated these findings using a cellular model with inducible T2E expression. Overexpression of miR-449a in vitro led to silencing of genes associated with NOTCH signaling (NOTCH1, HES1) and HDAC1. Interestingly, HDAC1 overexpression led to the repression of HES6, a negative regulator of the transcription factor HES1, the primary effector of NOTCH signaling, and promoted cell proliferation by repressing the cell cycle inhibitor p21. Inhibition of NOTCH as well as knockdown of HES1 reduced the oncogenic properties of PCa cell lines. Using tissue microarray analysis encompassing 533 human PCa cores, ERG-positive areas exhibited significantly increased HES1 expression. Taken together, our data suggest that an epigenomic regulatory network enhances NOTCH signaling and thereby contributes to the oncogenic properties of T2E+ PCa.

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

“…Moreover, a natural compound, genistein, inhibited cell growth and induced apoptosis in pancreatic cancer cells through the upregulation of miR-34a, leading to decreased Notch1 [ 76 ]. Regarding miR-449a, it has been recently reported that its overexpression in vitro led to the silencing of genes associated with Notch signaling in prostate cancer cells [ 77 ]. Consistent with these reports, we identified Notch as a direct target of miR-34a/c/miR-449a and provided new evidence that AdoMet was able to inhibit Notch expression through upregulation of miR-34a/c/miR-449a.…”

Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection

“…The differential activities of immunoprecipitated HDACs were not due to low immunoprecipitation efficiencies ( Figure 5 E). These results together suggest that DHOB, although used as an HDAC1 inhibitor ( Bauer et al., 2021 ; Bazou et al., 2016 ; Moon et al., 2017 ), targets both HDAC1 and HDAC2.

Figure 5 Mtb infection or stimulation induces elevated expression and activity of histone deacetylase in macrophages and DC, which is blocked by DHOB Human MDDC were infected H37Rv at 5 MOI for 16 h, and the expression of HDACs as indicated was determined by western blotting using GAPDH as loading control (A).

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“…The differential activities of immunoprecipitated HDACs were not due to low immunoprecipitation efficiencies (Figure 5E). These results together suggest that DHOB, although used as an HDAC1 inhibitor (Bauer et al, 2021;Bazou et al, 2016;Moon et al, 2017), targets both HDAC1 and HDAC2.…”

“…In the present study, by screening 11 zinc-dependent HDAC variants we identified that class I HDAC, except for HDAC8, are critical in regulation of IL-1β secretion by innate immune cells. By application of more specific inhibitors of class I HDACs, we found that DHOB previously used as HDAC1 inhibitor ( Bauer et al., 2021 ; Bazou et al., 2016 ; Moon et al., 2017 ) promotes the secretion of mature IL-1β in vitro by both human and mouse primary macrophages and DC and human cell lines in response to TLR4 stimulation and Mtb infection. However, based on molecular docking, DARTS and histone deacetylase activity analysis further revealed that DHOB has the potential to bind and inhibit both HDAC1 and HDAC2 deacetylase activities consistent with their shared high degree (>80%) of homology in amino acid sequences.…”

Treg-Derived Extracellular Vesicles: Roles in Diseases and Theranostics

“…miR-449a was found to be significantly highly expressed in EVs, which was reported to be suppressive to the inflammatory gene Notch1. 103 It has been proved that the anti-inflammatory properties possessed by the inhibition of Notch signaling in RA. 104 With comprehensive exploration, the anti-inflammatory effect exhibited by the inhibition of Notch signaling was performed by modulating the expansion and suppressive functions of Tregs.…”