An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFß Signaling.

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFß/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

GaN-based green resonant-cavity light-emitting diodes with Al mirror and copper plate.

In this Letter, GaN-based green resonant-cavity light-emitting diodes (RCLEDs) with a low-cost aluminum (Al) metal bottom mirror, a dielectric top mirror, and a copper (Cu) supporting plate were fabricated. The green-emitting epitaxial wafer was grown on a patterned sapphire substrate (PSS) to ensure high crystal quality (CQ). Laser lift-off (LLO) of the PSS and electrical plating of a Cu supporting plate were then carried out to realize the vertical device structure. The emission wavelength and full width at half maximum (FWHM) of the main emission peak of the device are ∼518 nm and 14 nm, respectively. Under the current density of 50 A/cm2, a relatively high light output power (LOP) of 11.1 mW can be obtained from the green RCLED. Moreover, when the current injection is 20 mA (8 A/cm2), the corresponding forward bias voltage is as low as ∼2.46 V. The reasons for the low operating voltage and high LOP can be attributed to the improvement of CQ, the release of residual compressive stress of the GaN-based epilayer due to the removal of PSS, and better heat dissipation properties of the Cu supporting plate.

VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic neoplastic disorder caused by germline mutation or deletion of the VHL gene, characterized by the tendency to develop multisystem benign or malignant tumors. The mechanism of VHL mutants in pathogenicity is poorly understand. RESULTS: Here we identified heterozygous missense mutations c.193T > C and c.194C > G in VHL in several patients from two Chinese families. These mutations are predicted to cause Serine (c.193T > C) to Proline and Tryptophan (c.194C > G) substitution at residue 65 of VHL protein (p.Ser65Pro and Ser65Trp). Ser65 residue, located within the ß-domain and nearby the interaction sites with hypoxia-inducing factor α (HIFα), is highly conserved among different species. We observed gain of functions in VHL mutations, thereby stabilizing HIF2α protein and reprograming HIF2α genome-wide target gene transcriptional programs. Further analysis of independent cohorts of patients with renal carcinoma revealed specific HIF2α gene expression signatures in the context of VHL Ser65Pro or Ser65Trp mutation, showing high correlations with hypoxia and epithelial-mesenchymal transition signaling activities and strong associations with poor prognosis. CONCLUSIONS: Together, our findings highlight the crucial role of pVHL-HIF dysregulation in VHL disease and strengthen the clinical relevance and significance of the missense mutations of Ser65 residue in pVHL in the familial VHL disease.

Mechanistic insights into genetic susceptibility to prostate cancer.

Prostate cancer (PCa) is the second most common cancer in men and is a highly heritable disease that affects millions of individuals worldwide. Genome-wide association studies have to date discovered nearly 270 genetic loci harboring hundreds of single nucleotide polymorphisms (SNPs) that are associated with PCa susceptibility. In contrast, the functional characterization of the mechanisms underlying PCa risk association is still growing. Given that PCa risk-associated SNPs are highly enriched in noncoding cis-regulatory genomic regions, accumulating evidence suggests a widespread modulation of transcription factor chromatin binding and allelic enhancer activity by these noncoding SNPs, thereby dysregulating gene expression. Emerging studies have shown that a proportion of noncoding variants can modulate the formation of transcription factor complexes at enhancers and CTCF-mediated 3D genome architecture. Interestingly, DNA methylation-regulated CTCF binding could orchestrate a long-range chromatin interaction between PCa risk enhancer and causative genes. Additionally, one-causal-variant-two-risk genes or multiple-risk-variant-multiple-genes are prevalent in some PCa risk-associated loci. In this review, we will discuss the current understanding of the general principles of SNP-mediated gene regulation, experimental advances, and functional evidence supporting the mechanistic roles of several PCa genetic loci with potential clinical impact on disease prevention and treatment.