19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML)

Lara, Joshua J.; Bencomo‐Alvarez, Alfonso E.; Gonzalez, Mayra A.; Olivas, Idaly M.; Young, James K.; López, José Luis Bello; Velazquez, Vanessa V.; Glovier, Steven; Keivan, Mehrshad; Rubio, Andres J.; Dang, Sara K.; Solecki, Jonathan P.; Allen, Jesse; Tapia, Desiree N.; Tychhon, Boranai; Astudillo, Gonzalo E.; Jordan, Connor; Chandrashekar, Darshan S.; Eiring, Anna M.

doi:10.3390/ijms232314586

Cited by 6 publications

(14 citation statements)

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“…For the 20S proteasome, PSMA4 , PSMA5 , PSMA7 , and all seven PSMB subunits are downregulated in AML versus normal controls ( Supplementary Figure S1 ). However, similar to our observations for PSMD3 ( 25 ), patients with higher expression levels tended to have worse outcomes ( Supplementary Figures S2, S3 ).…”

Section: Resultssupporting

confidence: 87%

“…Work from our lab and others had documented increased expression of several 19S proteasome subunits in multiple cancer types compared with normal tissue ( 24 , 49 , 51 , 57–60 ). Our previous work in AML studying the non-ATPase subunits of the 19S proteasome revealed that PSMD2 , PSMD3 , PSMD7 , and PSMD9 mRNA expression levels were reduced in AML versus normal progenitors, but that high levels of expression correlated with worse overall survival in AML patients ( 25 ). In fact, the downregulation of proteasome subunits is a universal feature of AML compared with normal mononuclear cells.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, the 19S complex contains numerous components subdivided into ATP-dependent and ATP-independent subunits ( Figure 1 ) ( 32 ). The ATP-dependent subunits include the proteasome 26S subunit, ATPases 1–6 (PSMC1-6, Supplementary Table S1 ), which make up the base of the 19S complex, whereas the ATP-independent subunits include proteasome 26S subunit, non-ATPases 1–16 (PSMD1-16) ( 25 ), which make up the 19S lid ( 33 ). The lid is important for interactions with ubiquitin, whereas the base is required for unfolding the protein to allow it to enter the 20S core ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

et al. 2023

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IntroductionThe ubiquitin-proteasome system (UPS) is an intracellular organelle responsible for targeted protein degradation, which represents a standard therapeutic target for many different human malignancies. Bortezomib, a reversible inhibitor of chymotrypsin-like proteasome activity, was first approved by the FDA in 2003 to treat multiple myeloma and is now used to treat a number of different cancers, including relapsed mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success, bortezomib and other proteasome inhibitors are subject to severe side effects, and ultimately, drug resistance. We recently reported an oncogenic role for non-ATPase members of the 19S proteasome in chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and several different solid tumors. In the present study, we hypothesized that ATPase members of the 19S proteasome would also serve as biomarkers and putative therapeutic targets in AML and multiple other cancers.MethodsWe used data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) available at UALCAN and/or GEPIA2 to assess the expression and prognostic value of proteasome 26S subunit, ATPases 1-6 (PSMC1-6) of the 19S proteasome in cancer. UALCAN was also used to associate PSMC1-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of PSMC genes across different cancer types.ResultsThe mRNA and protein expression of PSMC1-6 of the 19S proteasome were elevated in several cancers compared with normal controls, which often correlated with worse overall survival. In contrast, AML patients demonstrated reduced expression of these proteasome subunits compared with normal mononuclear cells. However, AML patients with high expression of PSMC2-5 had worse outcomes.DiscussionAltogether, our data suggest that components of the 19S proteasome could serve as prognostic biomarkers and novel therapeutic targets in AML and several other human malignancies.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

et al. 2023

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“…We found that the PSM family genes were a cluster, while the MCM family genes were a cluster. Moreover, both PSM and MCM family genes were associated with tumor progression [ 28 , 29 ]. Then, these genes were simplified by lasso regression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dual network analysis of transcriptome data for discovery of new therapeutic targets in non-small cell lung cancer

Bai,

Zhou,

Zhang

et al. 2023

Oncogene

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The drug therapy for non-small cell lung cancer (NSCLC) have always been issues of poisonous side effect, acquired drug resistance and narrow applicable population. In this study, we built a novel network analysis method (difference- correlation- enrichment- causality- node), which was based on the difference analysis, Spearman correlation network analysis, biological function analysis and Bayesian causality network analysis to discover new therapeutic target of NSCLC in the sequencing data of BEAS-2B and 7 NSCLC cell lines. Our results showed that, as a proteasome subunit coding gene in the central of cell cycle network, PSMD2 was associated with prognosis and was an independent prognostic factor for NSCLC patients. Knockout of PSMD2 inhibited the proliferation of NSCLC cells by inducing cell cycle arrest, and exhibited marked increase of cell cycle blocking protein p21, p27 and decrease of cell cycle driven protein CDK4, CDK6, CCND1 and CCNE1. IPA and molecular docking suggested bortezomib has stronger affinity to PSMD2 compared with reported targets PSMB1 and PSMB5. In vitro and In vivo experiments demonstrated the inhibitory effect of bortezomib in NSCLC with different driven mutations or with tyrosine kinase inhibitors resistance. Taken together, bortezomib could target PSMD2, PSMB1 and PSMB5 to inhibit the proteasome degradation of cell cycle check points, to block cell proliferation of NSCLC, which was potential optional drug for NSCLC patients.

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“…PSMD3 exerts an oncogenic effect on chronic myeloid leukemia (CML) by stabilizing of nuclear factor-kappa B [16], therefore, PSMD3 is considered as a potential target for anti-cancer therapeutics in CML [17]. High degrees of PSMD3 are related to a worse overall survival (OS) in FLT3 mutated AML, indicating that PSMD3 may act as a prognostic biomarker in AML [18]. Moreover, the expression of PSMD3 was significantly higher in breast cancer tissue compared to normal tissues.…”

Section: Introductionmentioning

confidence: 99%

PSMD3-ILF3 signaling cascade drives lung cancer cell proliferation and migration

Zhang

et al. 2023

Biol Direct

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Background Proteasome 26S subunit, non-ATPase 3 (PSMD3) has been reported to participate in various human cancers. Nevertheless, the function of PSMD3 in lung cancer (LC) remains unclear. Methods RT-qPCR and western blot were used to detect the expression of PSMD3 in LC tissues form TCGA database and clinical samples, and LC cell lines. To study the effect of PSMD3 on LC cell proliferation, migration, invasion, and apoptosis, siRNAs targeting PSMD3 were synthesized and overexpressed plasmids were constructed. CCK-8 assay, Transwell assay, and etc. were used to evaluate the results. Tumor xenograft model was used to evaluate the function of PSMD3 on tumor growth. CO-IP and MS were used to scan the proteins that bind with PSMD3. The interaction between PSMD3 and ILF3 in lung cancer cells were studied using IF staining, CHX protein stability, and ubiquitination assay. Additionally, the effect of ILF3 on cell progression and LC tumor growth was demonstrated by conducting a recovery assay using siILF3 and an ILF3 inhibitor YM155. Results We observed that PSMD3 was significantly overexpressed in LC tissues and cells, which indicated a poor prognosis. Meanwhile, we found that PSMD3 promoted cell proliferation, migration, and invasion of LC cells. We also determined that PSMD3 stabilized the protein expression of ILF3 and the deubiquitination of ILF3 in lung cancer cells. Furthermore, animal experiments showed that the ILF3 inhibitor YM155 could suppress tumor growth with the presence of PSMD3. Conclusions PSMD3 collectively regulated the stability of ILF3 protein and facilitated the ubiquitination of endogenous ILF3 in LC, which ultimately promoted the progression of LC cells. The PSMD3/ ILF3 axis could potentially be used as a novel strategy for both diagnosis and treatment of LC.

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19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML)

Cited by 6 publications

References 62 publications

The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

Dual network analysis of transcriptome data for discovery of new therapeutic targets in non-small cell lung cancer

PSMD3-ILF3 signaling cascade drives lung cancer cell proliferation and migration

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