Embryonic stem cells (ESCs) are refractory to inflammatory stimuli but acquire inflammatory competence upon differentiation, yet the underlying mechanisms remain unclear. Here, we report that H2BK5ac regulates the acquisition of inflammatory potential in mouse ESCs during differentiation. H2BK5ac levels increased at the regulatory regions of inflammatory genes upon differentiation, and this modification was required for their transcriptional upregulation. An acetylation-deficient H2BK5A mutant impaired the upregulation of inflammatory genes, whereas an acetylation-mimicking H2BK5Q mutant had the opposite effect. We identified p300 and HDAC3 as the acetyltransferase and deacetylase, respectively, that control H2BK5ac: p300 protein levels increased upon differentiation and its depletion reduced H2BK5ac levels, whereas loss of HDAC3 increased H2BK5ac levels despite its unchanged protein levels. H2BK5Q overexpression in mouse embryos increased embryonic mortality and inflammatory cytokine secretion, consistent with its pro-inflammatory effect. Thus, our study reveals H2BK5ac as a regulator that establishes inflammatory potential in mouse ESCs during differentiation.
Yan Xi, Shuai Pei, Qian-Qian Lou et al.· Cell Reports· 0 citations
Prostate cancer (PCa) is the second leading cause of cancer-related death among men worldwide. Although androgen deprivation therapy (ADT) effectively suppresses tumor growth, most patients eventually progress to castration-resistant prostate cancer (CRPC) and develop metastatic disease. The self-renewal, lineage plasticity, epithelial–mesenchymal transition (EMT), and bone metastatic capacity of prostate cancer stem cells (PCSCs) are central drivers of CRPC progression, therapeutic resistance, and metastasis, and the aberrant activation of the canonical Wnt signaling pathway plays a key regulatory role in this process. This review systematically discusses PCSC markers and their applications in clinical diagnosis, elucidates the molecular mechanisms by which aberrant activation of the canonical Wnt signaling pathway, induced by the synergistic effects of genetic mutations, non-coding RNA (ncRNA) dysregulation, epigenetic dysregulation, tumor microenvironment (TME) alterations, and synergistic crosstalk with androgen receptor (AR) signaling, PI3K/AKT/mTOR signaling, Hippo–YAP/TAZ signaling, and metabolic reprogramming, enhances the stemness of PCSCs and promotes their EMT and bone metastasis. We also summarize current research on therapeutic agents targeting the canonical Wnt signaling pathway to suppress PCSCs, along with major challenges in clinical translation and potential strategies to overcome them. Collectively, we propose that targeting this pathway to inhibit PCSCs represents a highly promising strategy for controlling CRPC progression, overcoming therapeutic resistance, and ultimately improving patient outcomes.
Hao-Ze Li, Hong-Tao Xu, Yifan Hou et al.· Journal of Translational Med...· 0 citations
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