Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance

Tai, Fang; Gong, Kunxiang; Song, Kai; He, Yan-Ling; Shi, Jian

doi:10.1038/s41467-019-14083-4

Cited by 21 publications

(19 citation statements)

References 47 publications

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“…Other studies reported JunD expression was increased in hearts from diet-induced obese mice, and regulated PPARc signaling leading to cardiac damage (44). miR-548d-3p directly targets JunD and loss of miR-548d-3p enhances JunD/RSK3 signaling in the chemotherapy resistant of breast cancer (45). JunD as a member of the transcription factors Activated Protein-1 (AP-1) family, is essential as a major gatekeeper in cell proliferation and fibrogenesis.…”

Section: Discussionmentioning

confidence: 99%

Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway

et al. 2021

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Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Long non-coding RNAs (lncRNAs) are regulators in DN progression. However, the regulatory mechanisms of multiple lncRNAs in DN remain to be determined. Our aim was to investigate the function and molecular mechanism of lncRNA RNA component of mitochondrial RNAase P (Rmrp) in DN. Here, we observed that the expression of Rmrp was up-regulated in the kidney of db/db DN mice and high glucose induced glomerular mesangial cells (MC). More importantly, the abnormal transcription of Rmrp was induced by nuclear transcription factor Sp1, which promotes the proliferation and production of fibrotic markers in MC. Subsequently, we screened the miRNAs related to Rmrp and found that Rmrp and miR-1a-3p are co-localized at the subcellular level of MC, and Rmrp could directly binds to miR-1a-3p. Further mechanism research demonstrated that the elevated miR-1a-3p significantly attenuated the proliferation and fibrosis-promoting effects induced by up-regulation of Rmrp. At the same time, we also investigated that miR-1a-3p can directly bind to Jun D proto-oncogene (JunD), thereby regulating the protein level of JunD. Rmrp-induced proliferation and fibrogenesis were reversed by co-transfection with JunD siRNA. In summary, Sp1 induced lncRNA Rmrp could drive the expression of JunD via sponging miR-1a-3p in DN progression.

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Section: Discussionmentioning

confidence: 99%

Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway

et al. 2021

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“…Non coding RNA (ncRNA) has been once considered as the "noise" of human genome transcription, which has no biological effects. With the development of high-throughput sequencing technology and in-depth research, more and more ncRNAs, especially miRNA and lncRNA, have been found to play very important roles in epigenetic regulation and take part in the occurrence and development of multiple diseases [22][23][24]. Although there have been some reports about ncRNAs in HSCR, its mode of action and mechanism still need further study [25,26].…”

Section: Discussionmentioning

confidence: 99%

lncRNA-RMST Functioned as a SOX2 Transcription Co-Regulator to Regulate miR-1251 in the Progression of Hirschsprung's Disease

Zhou

Zhi

Chen

et al. 2021

Preprint

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BackgroundHirschsprung’s disease (HSCR) is a congenital colon disease characterized by the lack of ganglion cells which is closely related to impaired migration and proliferation of enteric neural crest cells (ENCCs). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been authenticated as an important class of regulators of biological functions. In this study, a microarray analysis was conducted and found that Rhabdomyosarcoma 2-associated transcript (RMST), a newly defined lncRNA, was down-regulated in the stenotic segment of HSCR patients. MiR-1251 is transcribed from the intron region of RMST and was also low expressed in the aganglionic tract. This study aimed to clarify the roles they played in the occurrence of HSCR. MethodsQRT-PCR was applied to validate the mRNA expression of RMST, miR-1251, SOX2 and AHNAK, while western blotting was employed to evaluate the protein level of SOX2 and AHNAK in clinical samples and cells. CCK-8 and transwell assays were used to detect cell proliferation and migration after transfection. Chromatin immunoprecipitation (CHIP) was applied to confirm SOX2 could bind to the promoter region of miR-1251. RNA binding protein immunoprecipitation (RIP) was used to demonstrate the interaction between RMST and SOX2. Dul-luciferase reporter assay was performed to confirm miR-1251 could interact with AHNAK. ResultsWhen the expression of RMST or miR-1251 was reduced, cell proliferation and migration was attenuated. However, RMST not to influence the expression of miR-1251 directly. Through bioinformatic analysis, transcription factor SOX2 was predicted to bind to the promoter region of miR-1251 which was confirmed by CHIP assay. We also demonstrated that RMST exerted as a co-regulator of SOX2 via RIP assay. AHNAK was predicted as the downstream gene of miR-1251 confirmed by the dual-luciferase reporter assay. Furtherly, rescue experiments showed RMST functioned as a transcription co-regulator of SOX2 to upregulate the expression of downstream gene AHNAK by strengthening the regulation of SOX2 on miR-1251 in HSCR.ConclusionsThese findings uncovered the role of RMST/SOX2/miR-1251/AHNAK pathway during the development of Hirschsprung's disease and presented potential therapeutic targets for HSCR.

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“…JQ1 is the first drug that has been identified to inhibit the expression of C-MYC gene, an important oncogene, and had been thought to be a breakthrough in the field of tumor therapy. However, studies have indicated frequent resistance to JQ1 appeared in numerous tumor cells, so the exploration of resistance mechanism and combination therapy regimen have become the new hotspot [7][8][9][10][11]. The combination therapy focusing on the function of macrophages is few.…”

Section: Discussionmentioning

confidence: 99%

“…Many signal pathways are involved in subsequent downregulation of MYC-dependent genes and they interweave into a complicated network, thus various compensatory transcription mechanisms also evolved, leading to the resistance to JQ1 [6]. As the resistance to JQ1 appeared increasingly often, some studies have revealed the mechanism of resistance to JQ1, which varies in different tumor cells [7][8][9][10][11]. To improve the efficacy of JQ1, people try to combine JQ1 with other drugs and the regimens are destined to differ in different tumors.…”

Section: Introductionmentioning

confidence: 99%

JQ1 Synergize with Anti-CD47 Antibody to Enhance the Function of Macrophages and Repress the Progression of Burkitt Lymphoma

Wang¹,

Guo²,

Zhao³

et al. 2021

Preprint

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Background: M2 macrophages, as the most prominent immune cells in Burkitt lymphoma (BL), are promising targets and anti-CD47 antibody could enhance the phagocytosis but be unable to eradicate tumor cells. JQ1, a C-MYC inhibitor, may enhance the function of macrophages and be a choice for combination therapy. Methods: The effect JQ1, on the expression of CD47 was measured. Then the synergy of JQ1 and anti-CD47 antibody was measured using phagocytosis assays. The effect of JQ1 on the polarization of macrophages was also detected. Finally, the efficiency and safety of JQ1 and anti-CD47 antibody combination therapy was explored in a groin orthotopically implanted Raji tumor model. Results: JQ1 could suppress the expression of CD47 on the surface of BL cells, thus synergize with anti-CD47 antibody to enhance the phagocytosis of macrophages. JQ1 could polarize macrophages from M2 to M1 while inhibiting the proliferation, inducing the apoptosis and blocking the cell cycle of BL cells. Finally, JQ1 and anti-CD47 antibody combination therapy could repress the progression of BL in NOD/SCID mice. Conclusions: Macrophages may be a promising target in BL and JQ1 combined with anti-CD47 antibody may be a potential therapeutic choice, providing theoretical basis for the use of this new targeted immunotherapy in clinical practice.

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Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance

Cited by 21 publications

References 47 publications

Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway

Sp1-Induced lncRNA Rmrp Promotes Mesangial Cell Proliferation and Fibrosis in Diabetic Nephropathy by Modulating the miR-1a-3p/JunD Pathway

lncRNA-RMST Functioned as a SOX2 Transcription Co-Regulator to Regulate miR-1251 in the Progression of Hirschsprung's Disease

JQ1 Synergize with Anti-CD47 Antibody to Enhance the Function of Macrophages and Repress the Progression of Burkitt Lymphoma

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