The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity.

While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.

Osteoporosis screening using QCT-based cutoff value of Hounsfield units in patients with degenerative lumbar diseases.

PURPOSE: In patients with degenerative lumbar diseases, we aimed to establish the cutoff value of Hounsfield units (HU) for osteoporosis screening on the basis of the relationship between computed tomography (CT) HU value and volume bone mineral density (BMD) measured by quantitative computed tomography (QCT). METHODS: A total of 136 patients aged ≥ 50 years with degenerative lumbar diseases were retrospectively included. Their QCT-BMD of L1-2 were recorded, and the CT values of L1-2 were measured with the same CT images of QCT. The degree of bone loss was evaluated with the criteria based on QCT-BMD: cutoff value of 80 mg/cm3 for osteoporosis and cutoff value of 120 mg/cm3 for osteopenia. The cutoff of CT value was acquired according to the linear regression equation between CT value and QCT-BMD. RESULTS: The rate of osteoporosis, osteopenia, normal BMD was 33.8% (46/136), 51.5% (70/136), and 14.7% (20/136), respectively. The Pearson correlation coefficients between CT value and QCT-BMD were over 0.9 (P < 0.05). The cutoff of average CT value of L1-2 was calculated and adjusted to 110HU for osteoporosis and 160HU for osteopenia according the equation: average QCT-BMD of L1-2 = 0.76 âœ• average CT value of L1-2-0.46 (R2 = 0.931, P < 0.001). Cutoff value of 110HU was 91.2% (42/46) sensitive and 88.9% (80/90) specific for identifying osteoporosis. The cutoff value of 160HU was 95.0% (19/20) sensitive and 96.6% (112/116) specific for distinguishing normal BMD from abnormal BMD (osteoporosis and osteopenia). CONCLUSION: The CT value is effective in osteoporosis screening, and the QCT-based cutoff value is 110 HU for osteoporosis and 160 HU for osteopenia in the patients with degenerative lumbar disease.

USP9X-mediated deubiquitination of B-cell CLL/lymphoma 9 potentiates Wnt signaling and promotes breast carcinogenesis.

Hyperactivation of the canonical Wnt-signaling pathway is a prominent feature of a number of human malignancies. Transcriptional activation of this signaling cascade depends on the formation of the ß-catenin-B-cell CLL/lymphoma 9 (BCL9)-pygopus (PYGO) family plant homeodomain finger 1 complex, yet how the assembly of this complex is regulated remains to be investigated. Here, using MCF-7, HeLa, HEK293T, MDA-MB-231, and Sf9 cells, along with immunoblotting and immunofluorescence, nano-HPLC-MS/MS, deubiquitination, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assays, we report that BCL9 physically associates with a protein deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), and that USP9X removes Lys-63-linked polyubiquitin on Lys-212 of BCL9. Importantly, the USP9X-mediated BCL9 deubiquitination facilitated the formation of the ß-catenin-BCL9-PYGO complex, thereby potentiating the transcriptional activation of Wnt/ß-catenin target genes. We also show that USP9X-mediated BCL9 deubiquitination promotes the proliferation and invasion of breast cancer cells. Together, these results uncover USP9X as a deubiquitinase of BCL9, implicating USP9X in Wnt/ß-catenin signaling and breast carcinogenesis.