Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

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 results in dephorphorylation of 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.

Grantor dc:publisher

Temple University. Libraries

Year dc:date.issued

2017

Author dc:creator

• Zhang, Hanghang

Advisor dc:contributor.advisor

• Issa, Jean-Pierre

Committee members dc:contributor.committeemember

• Sapienza, Carmen
• Graña-Amat, Xavier
• Jacobson, Marlene A.

• Oncology
• Pharmacology
• Genetics
• CDK9
• DNA methylation
• Epigenetic therapy
• Gene silencing
• Immunosensitization

Statement dc:rights

• IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/20.500.12613/4092

OAI identifier oai:identifier

oai:scholarshare.temple.edu:20.500.12613/4092