Role of genome organization and TOP2B in androgen signaling, transcription, and genomic rearrangements and genomic instability

Androgen receptor (AR) signaling is critical to the pathogenesis of prostate cancer and AR is a critical therapeutic target in prostate cancer. Androgen receptor (AR) signaling involves a complex and coordinated series of events that include binding of androgen hormones by the receptor, binding of the liganded receptor complex to diverse sites on the genome, and dynamic reorganization of the genome to facilitate efficient target gene expression. We have recently shown that topoisomerase II beta (TOP2B) is co-recruited with AR to target sites and that its recruitment and catalytic activity are required for efficient AR target gene expression. We have also shown that androgen stimulation promotes co-recruitment of AR and TOP2B to sites of recurrent rearrangement breakpoints in prostate cancer, triggering recombinogenic TOP2B-mediated double strand breaks. These data suggest that androgen signaling and associated intrinsic transcriptional programs require TOP2B, and also that such processes can be corrupted, leading to TOP2B-mediated genomic breaks that may ultimately nucleate genomic rearrangements in prostate and other cancers.

Based on these data, we hypothesize that TOP2B may be involved in relieving topological constraints during genomic reorganization induced by androgen signaling/stimulation. Furthermore, we hypothesize that the need to re-establish this genomic reorganization after every cell division may make proliferating cancer cells more prone to developing TOP2B-mediated double strand breaks that may contribute to genomic instability. Finally, we hypothesize that it may be possible to target these transcription-associated double strand breaks as an achilles heel in cancer therapy.

Targeting epigenetic alterations for cancer therapy

Epigenetic gene silencing ubiquitously accompanies the development of prostate cancer (and other human cancers); reactivation of silenced genes has emerged as a rational treatment strategy. Unfortunately, epigenetic drugs have only had limited success as single agent therapies for human cancers including prostate cancer, and there has been a somewhat haphazard approach to empirically identify drug combinations that may synergize with epigenetic drugs. In a collaboration with Bill Nelson’s laboratory, we have developed a novel, rational, approach to identification of effective drug combinations with epigenetic drugs that can induce synthetic lethality in human cancers.

Development of biomarkers for prostate cancer diagnosis and risk stratification

There is a critical need for biomarkers for accurate prostate cancer diagnosis and risk stratification.

Understanding the complex interplay of genetic and epigenetic processes in establishing and maintaining the neoplastic phenotype

It is now clear that cancer initiation and progression occurs through the acquisition of somatic genome alterations at both the genetic and epigenetic levels. Interestingly, genetic and epigenetic processes are often seen to cooperate to establish and maintain the neoplastic phenotype in cancer cells. While much recent effort has focused on understanding the inherited and somatic genetic alterations occurring in human cancer, it is becoming clear that this is an incomplete picture without the simultaneous and integrated understanding of epigenetic alterations. A major limitation has been the lack of robust, cost-effective, quantitative and integrative technologies for the assessment of epigenetic processes alongside the genetic processes.

We have developed and optimized a novel suite of technologies that harness the power of microarrays and next generation sequencing for integrated, cost-effective, and quantitative measurement of genetic and epigenetic alterations. We are currently applying these technologies to understand the cooperation of genetic alterations, such as mutations, deletions, amplifications, and rearrangements, with epigenetic alterations, such as DNA methylation changes, in prostate carcinogenesis and disease progression. These analyses have helped identify novel putative oncogenes and tumor suppressor and metastasis suppressor genes that we are currently functionally characterizing. In addition to providing insights into cancer biology, these analyses have helped to nominate several DNA based biomarkers for prostate cancer detection, risk stratification, and prediction of treatment response.

Srinivasan (Vasan) Yegnasubramanian, M.D., Ph.D.
Assistant Professor of Oncology
Johns Hopkins University

Sidney Kimmel Comprehensive Cancer Center
Cancer Research Building II, Room 145
1550 Orleans Street
Baltimore, MD, 21231