Proteasome 26S Subunit, non-ATPase 3 (PSMD3) Regulates Breast Cancer by Stabilizing HER2 from Degradation

Abstract

It is well-known that human epidermal growth factor receptor 2 (HER2) is critical for breast cancer (BC) development and progression. Several studies have revealed the role of the ubiquitin/proteasome system (UPS) in cancer. In this study, we investigated the expression level of Proteasome 26S subunit, non-ATPase 3 (PSMD3) in BC using BC cell lines, human BC tissue samples, Oncomine, and TCGA databases and studied the PSMD3-HER2 protein interaction. PSMD3 was upregulated in BC, particularly in the HER2+ subtype. PSMD3 immunostaining was detected in the cytoplasm and nucleus of BC tumor tissues. Strong interaction between PSMD3 and HER2 at the protein level was observed. Knockdown of PSMD3 significantly impaired the stability of HER2, inhibited BC cell proliferation and colony formation, and induced cell apoptosis. Ubiquitination process was strongly enhanced after knockdown of PSMD3 in association with decreased HER2 level. Accumulation and Localization of LAMP-1 in the cell membrane with decreased HER2 immunostaining was observed after knockdown of PSMD3. High expression level of PSMD3 was associated with HER2 expression (p < 0.001), tumor size (p < 0.001), and clinical stage (p = 0.036). High expression level of PSMD3 predicted a short overall survival (OS), particularly for HER2+. Overall, we provide a novel function for PSMD3 in stabilizing HER2 from degradation in HER2+ BC, which suggests that PSMD3 is a novel target for HER2+ BC.

Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

“…Genes including PSMD3 , TXN , GSTP1 and HMGB1&3 were downregulated in the radiation group and upregulated in the torpor + radiation groups. PSMD3 is a component of the proteasome involved in removing damaged or unfolded proteins, consistent with the reported enrichment of ER-associated degradation pathway [ 93 ]. Additionally, TXN has previously been shown to confer radio-resistance and mitigate radiation-induced lethality [ 94 ].…”

Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B

“…3C, PSMD3 protein in CML CD34 + cells migrated farther on the gel than PSMD3 in cord blood, suggesting aberrant PTMs. In breast cancer, PSMD1 was shown to induce p53 protein degradation [30], whereas PSMD3 protected HER2 from degradation in HER2-positive breast cancers [31]. We propose that PSMD1 and PSMD3 protect NF-κB protein from degradation.…”

“…1 and Supplementary Table S5), identifying PSMD1 and PSMD3. PSMD1 and PSMD3 are non-ATPase subunits in the 19S regulatory complex of the UPS, which regulate proteasome substrate recognition and binding [30,31]. To date, the role of PSMD1 and PSMD3 in CML and NF-κB activation remains unknown.…”

“…They were also identified as survival-critical genes in a previously published small hairpin RNA (shRNA) library screen for TKI resistance [29]. PSMD1 and PSMD3 are members of the 19S regulatory complex in the 26S proteasome, regulating substrate recognition and binding [30,31]. In breast cancer, PSMD1 promoted cancer cell growth by inducing p53 protein degradation [30]; PSMD3, in contrast, enhanced cancer cell growth by stabilizing human epidermal growth factor receptor 2 (HER2) from degradation [31].…”

“…PSMD1 and PSMD3 are members of the 19S regulatory complex in the 26S proteasome, regulating substrate recognition and binding [30,31]. In breast cancer, PSMD1 promoted cancer cell growth by inducing p53 protein degradation [30]; PSMD3, in contrast, enhanced cancer cell growth by stabilizing human epidermal growth factor receptor 2 (HER2) from degradation [31]. In acute myeloid leukemia (AML), patients with higher levels of PSMD3 mRNA were shown to have a worse overall survival than patients with lower levels of expression [32].…”