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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

ABSTRACT: BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

PROVIDER: PRJNA1000553 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25467600_1.fastq.gz	Fastqsanger.gz
	SRR25467600_2.fastq.gz	Fastqsanger.gz
	SRR25467601_1.fastq.gz	Fastqsanger.gz
	SRR25467601_2.fastq.gz	Fastqsanger.gz
	SRR25467602_1.fastq.gz	Fastqsanger.gz

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

Project description:In colorectal cancer (CRC), WNT/β-catenin signaling is aberrantly activated mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are under pre-clinical and clinical trials, while their resistance mechanisms remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cells were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations (i.e., bell-shaped dose response: BSDR). Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in the BSDR cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Taken together, these observations suggest that combination of tankyrase and BET inhibitors would be a useful therapeutic approach to overcome a subset of resistance to tankyrase inhibitors.

2024-07-29 | GSE239681 | GEO

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

Project description:BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

| PRJNA1000550 | ENA

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

Project description:BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

| PRJNA1000562 | ENA

Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress APC-mutated colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived APC-mutated CRC cells (JC21 and JC475) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-07-29 | GSE239683 | GEO

Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

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Gene expression profiling of tankyrase-inhibited mouse articular chondrocytes

Project description:Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically-induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.

2019-09-24 | GSE137899 | GEO

Gene expression data of colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived CRC cells (JC11 and JC494) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.

2024-01-17 | GSE217758 | GEO

Proteomic profiling of Palbociclib arrested cells ± APC/C inactivation.

Project description:Cellular proliferation is highly regulated to ensure proper tissue homeostasis and to prevent diseases such as cancer. In actively proliferating cells, entry into S phase of the cell cycle and initiation of DNA replication is promoted by inactivation of the E3 ubiquitin ligase APC/C (anaphase promoting complex/cyclosome), though the critical S phase-promoting substrates have not been fully elucidated. The APC/C is also active in cells that have exited the cell cycle and entered an arrested state, but whether APC/C activity is essential to maintain arrest is unclear. We found that APC/C inactivation is sufficient to bypass cellular arrest induced by the CDK4/6 inhibitor Palbociclib. To identify potential APC/C substrates responsible for driving the escape from cell cycle arrest, we arrested cells using Palbociclib and then induced EMI1, inactivating the APC/C. Samples were collected at 0, 8, 16 and 20h after arrest and analyzed using proteomics. We found that inactivation of the APC/C promotes cell cycle re-entry by inducing RB phosphorylation and E2F-dependent gene transcription. Stabilization of both cyclin A and cyclin B contributes to arrest bypass, but only cyclin A accumulation is absolutely required. Direct expression of APC/C-resistant cyclin A, but not cyclin B, in arrested cells induces S phase entry analogous to APC/C inactivation. Cells bypassing arrest initiate DNA replication with severely reduced origin licensing, at least in part due to premature geminin accumulation. As a result, cells exhibit reduced rates of DNA synthesis, which leads to the accumulation of replication stress and long-term proliferation defects. Our findings suggest that CDK4/6 inhibition in cancers with reduced APC/C activity may be ineffective at promoting cytostatic cell cycle arrest but may nonetheless lead to elevated levels of replication stress that ultimately leads to a more durable cell cycle withdrawal.

2024-07-18 | PXD046783 | Pride

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