Abstract P150: PSMD1 and PSMD3 as putative targets for cancer therapy

Abstract

Abstract Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a result, the anticancer drugs bortezomib, carfilzomib, and ixazomib targeting the 26S proteasome were developed to treat multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success demonstrated by these treatments, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options. The 26S proteasome is composed of two 19S regulatory subunits and a 20S catalytic core, leaving ample opportunity for new targets. We recently demonstrated that knockdown of the 19S regulatory subunits, proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), resulted in increased apoptosis of tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cells, but had no effect on normal cord blood controls, suggesting they may be good targets for therapy. Therefore, we hypothesized that PSMD1 and PSMD3 are potential targets for anticancer therapeutics and that their relevance stretches beyond CML to other types of cancers. In the present study, we analyzed PSMD1 and PSMD3 expression in other types of cancers versus normal controls using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), comparing expression with overall survival (OS). Data were analyzed using UALCAN (http://ualcan.path.uab.edu) and GEPIA2 (http://gepia2.cancer-pku.cn/). At the mRNA level, PSMD1 was found to be overexpressed in 14/24 (58%) TCGA cancers compared with normal controls. This was confirmed at the protein level for breast (p=4.2e-4), colon (p=7.1e-20), clear cell renal carcinoma (p=1.8e-4), and endometrial cancer (p=2.0e-22). PSMD3 was found upregulated at the mRNA level in 18/24 (75%) TCGA cancers, which was confirmed at the protein level in breast (p=8.3e-4), colon (p=1.0e-27), ovarian (p=4.2e-6), clear cell renal carcinoma (p=4.0e-19), and endometrial cancer (p=1.5e-19). Upon correlation of PSMD1 expression with OS, we saw that when overexpressed, individuals did significantly worse with adrenocortical carcinoma, lower grade glioma, lung adenocarcinoma, mesothelioma, and uveal melanoma. In contrast, diffuse large B cell lymphoma (DLBCL) and stomach adenocarcinoma patients with lower PSMD1 expression had a worse OS. Similarly, patients with high levels of PSMD3 mRNA expression had a significantly worse OS in kidney chromophobe, skin cutaneous melanoma, uveal melanoma, and mesothelioma. Our analysis revealed that differential expression of PSMD1 and PSMD3 is correlated with survival in several different cancer types. Future directions will identify PSMD1 and PSMD3 post-translational modifications that may be novel targets for anticancer therapeutics. In conclusion, we highlight PSMD1 and PSMD3 as potential therapeutic targets for the development of novel proteasome inhibitors to treat cancer patients with less toxicity. Citation Format: Andres J. Rubio, Alfonso E. Bencomo-Alvarez, James E. Young, Vanessa V. Velazquez, Anna M. Eiring. PSMD1 and PSMD3 as putative targets for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P150.