Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Venkadakrishnan, Varadha Balaji; Presser, Adam G.; Singh, Richa; Booker, Matthew A.; Traphagen, Nicole A.; Weng, Kenny; Voss, Nathaniel C. E.; Mahadevan, Navin R.; Mizuno, Kei; Puca, Loredana; Idahor, Osasenaga; Ku, Sheng-Yu; Bakht, Martin K.; Borah, Ashir A.; Herbert, Zachary T.; Tolstorukov, Michael Y.; Barbie, David A.; Rickman, David S.; Brown, Myles; Beltran, Himisha

doi:10.1038/s41467-024-51156-5

Cited by 5 publications

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Personalized Medicine: Leave no Patient Behind; Report From the 2024 Coffey‐Holden Prostate Cancer Academy Meeting

Miyahira,

Sharifi,

Chesner

et al. 2024

The Prostate

View full text Add to dashboard Cite

IntroductionThe 11th Annual 2024 Coffey ‐ Holden Prostate Cancer Academy (CHPCA) Meeting, was themed “Personalized Medicine: Leave No Patient Behind,” and was held from June 20 to 23, 2024 at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA.MethodsThe CHPCA Meeting is an academy‐styled annual conference organized by the Prostate Cancer Foundation, to focus discussion on the most critical emerging research that have the greatest potential to advance knowledge of prostate cancer biology and treatment. The 2024 CHPCA Meeting was attended by 75 academic investigators and included 37 talks across 8 sessions.ResultsThe meeting sessions focused on: novel human, mouse and systems biology research models, novel immunotherapies for prostate cancer, efforts to overcome treatment resistance, the role of metabolism and diet in prostate cancer biology and as a therapeutic target, mechanisms that drive differentiation into neuroendocrine cancer subtypes, the evolving prostate cancer epigenome in disease progression and treatment resistance, and machine learning and advanced computational approaches for precision oncology.DiscussionThis article summarizes the presentations and discussions from the 2024 CHPCA Meeting. We hope that sharing this knowledge will inspire and accelerate research into new discoveries and solutions for prostate cancer.

show abstract

Personalized Medicine: Leave no Patient Behind; Report From the 2024 Coffey‐Holden Prostate Cancer Academy Meeting

Miyahira,

Sharifi,

Chesner

et al. 2024

The Prostate

View full text Add to dashboard Cite

show abstract

Understanding the development of enzalutamide resistance based on a functional single-cell approach

Xue,

Ko,

Shi

et al. 2024

Preprint

View full text Add to dashboard Cite

Most metastatic prostate cancers (PCa) initially depend on androgen for survival and proliferation. Thus, antiandrogen or castration therapies are the mainstay treatment. Although effective at first, androgen dependent PCa (ADPC) universally develops therapy resistance, thereby evolving to the incurable disease, called castration resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear. We used single cell RNA sequencing (scRNA-Seq) to determine how a therapy-naive ADPC cell line LNCaP responds to the anti-androgen drug, enzalutamide. We found that most cells expressed the drug target androgen receptor (AR+), while a small subpopulation (~12%) expressed low or no AR (ARlow/none). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/none cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/none cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolate ARlow/none and AR+ cells from the LNCaP cell line, and functionally confirmed the enzalutamide resistant phenotype of ARlow/none cells in vitro and in xenograft models in vivo. Finally, to explore a therapeutic option for ARlow/none cells, we found that ARlow/none cells expressed low levels of NAD+ biosynthesis genes, notably NAPRT, indicating a possible vulnerability to inhibitors blocking NAD+ synthesis. Indeed, treating ARlow/none cells with NAD+ synthesis inhibitors, FK866 and OT82, significantly inhibited the survival and proliferation of ARlow/none cells, thus suggesting a possible novel therapeutic option for ADT and enzalutamide resistant PCa.

show abstract

Chromatin remodeling restraints oncogenic functions in prostate cancer

Lanzuolo,

Rosti,

Petrini

et al. 2024

Preprint

View full text Add to dashboard Cite

Primary prostate cancer (PCa) is characterized by multifocal growth and a highly variable clinical course, which is not effectively predicted by prognostic screenings. Innovative strategies for the stratification of primary prostate cancers are still needed. Using prostate biopsies, we analyzed the epigenome of 17 chemo-naïve patients with putative PCa for genome-wide mapping of heterochromatic and euchromatic domains, as well as their three-dimensional (3D) compartmentalization in the cell nucleus. We identified two subgroups of cancer patients with different degrees of chromatin 3D architecture and transcriptome alterations: the LDD (Low Degree of Decompartmentalization) and HDD (High Degree of Decompartmentalization) groups. HDD subtype exhibits an extensive chromatin reorganization that restrains tumor potential, by repressing pathways related to extracellular matrix remodeling and phenotypic plasticity. We derived an 18-genes transcriptional signature that distinguishes HDD from LDD subtype and we confirmed its prognostic relevance across multiple cohorts covering more than 900 prostate cancer patients in total. We propose this transcriptional signature derived from chromatin compartmentalization analysis as a novel prognostic tool that could be adopted at the time of the diagnostic prostate biopsy.

show abstract

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Cited by 5 publications

References 65 publications

Personalized Medicine: Leave no Patient Behind; Report From the 2024 Coffey‐Holden Prostate Cancer Academy Meeting

Personalized Medicine: Leave no Patient Behind; Report From the 2024 Coffey‐Holden Prostate Cancer Academy Meeting

Understanding the development of enzalutamide resistance based on a functional single-cell approach

Chromatin remodeling restraints oncogenic functions in prostate cancer

Contact Info

Product

Resources

About