271P - Prostate cancer with histone modifier UTX mutations can benefit from olaparib

Background

Histone modifications are important for tissue homeostasis, and their mutations are involved in carcinogenesis. Mutations in a histone modifier, UTX (also known as KDM6A), and loss of its counterpart UTY (also known as KDM6C) are common in prostate cancer (PCa). However, mechanisms of carcinoma development and drug sensitivity in UTX-deficient PCa are not clear. We hypothesized that elucidating the mechanism of carcinogenesis by loss of UTX may develop novel molecular targeted therapies for UTX-deficient PCa.

Methods

We generated genetically-engineered mice with deletion of both Utx and Uty in the prostate tissue (UtxΔ, UtyΔ) and crossed with mice with a heterozygous deletion of p53 (p53+/−) to create UtxΔ, UtyΔ and p53+/− compound mice. Mice were administered a high-fat diet (HFD) starting at 8 weeks of age to promote cancer growth by inflammation. We found the development of PCa with Gleason score (GS) = 3+3 at 4 months after HFD treatment. Isolated prostate tissues were subjected to pathologic, molecular, and cellular analyses. RM-2 mouse PCa cells which do not express UTY were knocked down for Utx (siUtx) and control (siNC) by siRNAs to assess changes in the abilities of proliferation and migration.

Results

RM-2 siUtx cells showed increased proliferation and migration abilities compared with RM-2 siNC cells. By performing high-throughput RNA sequencing (RNA seq) and gene set enrichment analysis (GSEA) using mouse prostate tissues, we found that loss of UTX inactivated a pathway for DNA damage repair such as ATM pathway. To confirm this, we irradiated Utx+, UtyΔ, p53+/− mice and UtxΔ, UtyΔ, p53+/− mice and found that the time required for DNA damage repair was prolonged in UtxΔ, UtyΔ, p53+/− mice compared with Utx+, UtyΔ, p53+/− mice by immunofluorescent staining with an antibody against γH2AX, a marker of DNA repair. We also found that olaparib inhibited proliferation with RM-2 siUtxcells compared with RM-2 siNC cells.

Conclusions

Inactivation of the DNA damage repair pathway was suggested as one of the oncogenic mechanisms of UTX-deficient PCa. Moreover, olaparib may be effective in the treatment of PCa with loss of UTX function. Since loss of UTX function has also been observed in other types cancers, our therapeutic strategy may apply for other UTX-deficient cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.