The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is implicated in active transcription. Here we show that DOT1L is overexpressed in Prostate cancer (PCa) and is associated with poor clinical outcome. Genetic and chemical inhibition of DOT1L selectively impaired viability of androgen receptor (AR)-signaling competent PCa cells, including castration-resistant and enzalutamide-resistant cells. DOT1L inhibition led to loss of H3K79 methylation at distinct genomic loci in AR-positive compared to AR-negative PCa cells. The selective sensitivity to DOT1L inhibition is in part due to loss of MYC expression caused by displacement of AR and DOT1L at a distal enhancer. Furthermore, loss of MYC expression leads to upregulation of E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC protein degradation. This leads to further repression of the MYC pathway in a negative feed forward manner. These results demonstrate that DOT1L selectively regulates the tumorigenicity of AR-positive PCa cells and provide a rationale for investigating DOT1L inhibition as a promising therapeutic strategy for PCa.

Creator

• Vatapalli, Rajita

DOI

• https://doi.org/10.21985/n2-crdc-nd30

Subject

• Molecular biology
• Oncology

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:14971
• etdadmin_upload_714534

Keyword

• Prostate Cancer
• DOT1L
• Epigenetics

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright