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

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma (PRAD) and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Significance of RB Loss in Unlocking Phenotypic Plasticity in Advanced Cancers.

Cancer cells can undergo plasticity in response to environmental stimuli or under selective therapeutic pressures that result in changes in phenotype. This complex phenomenon of phenotypic plasticity is now recognized as a hallmark of cancer. Lineage plasticity is often associated with loss of dependence on the original oncogenic driver and is facilitated, in part, by underlying genomic and epigenetic alterations. Understanding the molecular drivers of cancer plasticity is critical for the development of novel therapeutic strategies. The retinoblastoma gene RB1 (encoding RB) is the first tumor suppressor gene to be discovered and has a well-described role in cell-cycle regulation. RB is also involved in diverse cellular functions beyond cell cycle including differentiation. Here, we describe the emerging role of RB loss in unlocking cancer phenotypic plasticity and driving therapy resistance across cancer types. We highlight parallels in cancer with the noncanonical role of RB that is critical for normal development and lineage specification, and the downstream consequences of RB loss including epigenetic reprogramming and chromatin reorganization that can lead to changes in lineage program. Finally, we discuss potential therapeutic approaches geared toward RB loss cancers undergoing lineage reprogramming.

COVID-19 shines a light on health inequities in communities of color: A youth-driven photovoice inquiry.

This manuscript reports on a youth-driven health assessment engaging youth of color in identifying community health priorities during the coronavirus disease 2019 (COVID-19) pandemic. Photovoice, a participatory visual ethnographic health assessment strategy, was used to explore the question: What does health or healthiness mean to you and/or your community? Youth captured images that represented their priorities. The photos were discussed using the SHOWed framework and analyzed thematically. Four themes related to community health were identified. Additionally, youth captured their narrative of COVID-19 as "a revealing force that highlights systemic inequities, driving individuals and communities to both cultivate their resilience and take healthcare into their own hands in response to government and policy level failures." Youth are acutely aware of the historical and structural inequities that create multi-level barriers to healthcare access. Health inequities existed long before the pandemic, but the current crisis requires us to examine ways to transform the healthcare landscape moving forward.