Dataset Information

SMARCA4_Phosphopeptide

ABSTRACT: Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition dephosphorylates the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Colon Cancer

SUBMITTER: Carlos Barrero

LAB HEAD: Salim Merali

PROVIDER: PXD009573 | Pride | 2020-05-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	ELITE_JP_SMARCA4MC180295_1HOUR_BUFFERX.raw	Raw
	ELITE_JP_SMARCA4MC180295_30MINS_BUFFERX.raw	Raw
	ELITE_JP_SMARCA4_1HOUR_BUFFERX.raw	Raw
	ELITE_JP_SMARCA4_30MINS_BUFFERX.raw	Raw
	ELITE_JP_SMARCA4_ALONE_BUFFERX.raw	Raw

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Publications

Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.

Zhang Hanghang H Pandey Somnath S Travers Meghan M Sun Hongxing H Morton George G Madzo Jozef J Chung Woonbok W Khowsathit Jittasak J Perez-Leal Oscar O Barrero Carlos A CA Merali Carmen C Okamoto Yasuyuki Y Sato Takahiro T Pan Joshua J Garriga Judit J Bhanu Natarajan V NV Simithy Johayra J Patel Bela B Huang Jian J Raynal Noël J-M NJ Garcia Benjamin A BA Jacobson Marlene A MA Kadoch Cigall C Merali Salim S Zhang Yi Y Childers Wayne W Abou-Gharbia Magid M Karanicolas John J Baylin Stephen B SB Zahnow Cynthia A CA Jelinek Jaroslav J Graña Xavier X Issa Jean-Pierre J JJ

Cell 20181025 5

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates ...[more]

PMID: 30454645

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Project description:Background: Prion diseases such as bovine spongiform encephalopathies (BSE) are transmissible neurodegenerative diseases which are presumably caused by an infectious conformational isoform of the cellular prion protein. Previous work has provided evidence that in murine prion disease the endogenous retrovirus (ERV) expression is altered in the brain. To determine if prion-induced changes in ERV expression are a general phenomenon we used a non-human primate model for prion disease. Results: Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. We could show that Class I gammaretroviruses HERV-E4-1, ERV-9, and MacERV-4 increase expression in BSE-infected macaques. In a second approach, we analysed ERV-K-(HML-2) RNA and protein expression in extracts from the same cynomolgus macaques. Here we found a significant downregulation of both, the macaque ERV-K-(HML-2) Gag protein and RNA in the frontal/parietal cortex of BSE-infected macaques. Conclusions: We provide evidence that dysregulation of ERVs in response to BSE-infection can be detected on both, the RNA and the protein level. To our knowledge, this is the first report on the differential expression of ERV-derived structural proteins in prion disorders. Our findings suggest that endogenous retroviruses may induce or exacerbate the pathological consequences of prion-associated neurodegeneration. Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. In a second approach, ERV-K-(HML-2) RNA and protein expression was analysed in extracts from the same cynomolgus macaques.