Loss of Correlated Proteasomal Subunit Expression Selectively Promotes the 20S State Which Underlies Luminal Breast Tumorigenicity

Overview

Journal Commun Biol

Date 2025 Jan 15

PMID 39814910

Authors

Rangapriya Sundararajan

Shubhada R Hegde

Ashish Kumar Panda

Joel Christie

Nikhil Gadewal

Prasanna Venkatraman

Affiliations

Soon will be listed here.

Abstract

Why cancer cells disproportionately accumulate polyubiquitinated proteotoxic proteins despite high proteasomal activity is an outstanding question. While mis-regulated ubiquitination is a contributing factor, here we show that a structurally-perturbed and sub-optimally functioning proteasome is at the core of altered proteostasis in tumors. By integrating the gene coexpression signatures of proteasomal subunits in breast cancer (BrCa) patient tissues with the atomistic details of 26S holocomplex, we find that the transcriptional deregulation induced-stoichiometric imbalances perpetuate with disease severity. As seen in luminal BrCa cell lines, this imbalance limits the number of double-capped 19S-20S-19S holocomplexes (30S) formed and promotes free 20S catalytic core accumulation that is widely-believed to confer survival advantage to tumors. By retaining connectivity with key tumor 19S:20S interface nodes, the PSMD9 19S subunit chaperone emerges as a crucial regulator of 26S/30S:20S ratios sustaining tumor cell proteasome function. Disrupting this connectivity by depleting PSMD9 in MCF7 cells introduces structural anomalies in the proteasome, and shifts dependence from 20S to a deregulated 26S state invoking anti-tumor responses which opens up clinically-relevant therapeutic possibilities.

References

Tyanova S, Albrechtsen R, Kronqvist P, Cox J, Mann M, Geiger T . Proteomic maps of breast cancer subtypes. Nat Commun. 2016; 7:10259. PMC: 4725767. DOI: 10.1038/ncomms10259. View

Ren C, Yang L, Liu L, Chen Y, Cheng G, Zhang X . Effects of shRNA-mediated silencing of PSMA7 on cell proliferation and vascular endothelial growth factor expression via the ubiquitin-proteasome pathway in cervical cancer. J Cell Physiol. 2017; 234(5):5851-5862. DOI: 10.1002/jcp.26408. View

Huang X, Luan B, Wu J, Shi Y . An atomic structure of the human 26S proteasome. Nat Struct Mol Biol. 2016; 23(9):778-85. DOI: 10.1038/nsmb.3273. View

Nahar A, Fu X, Polovin G, Orth J, Park S . Two alternative mechanisms regulate the onset of chaperone-mediated assembly of the proteasomal ATPases. J Biol Chem. 2019; 294(16):6562-6577. PMC: 6484131. DOI: 10.1074/jbc.RA118.006298. View

Tsvetkov P, Mendillo M, Zhao J, Carette J, Merrill P, Cikes D . Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome. Elife. 2015; 4. PMC: 4551903. DOI: 10.7554/eLife.08467. View

Tsvetkov P, Sokol E, Jin D, Brune Z, Thiru P, Ghandi M . Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. Proc Natl Acad Sci U S A. 2016; 114(2):382-387. PMC: 5240730. DOI: 10.1073/pnas.1619067114. View

Almond J, Cohen G . The proteasome: a novel target for cancer chemotherapy. Leukemia. 2002; 16(4):433-43. DOI: 10.1038/sj.leu.2402417. View

Kumatori A, Tanaka K, Inamura N, Sone S, Ogura T, Matsumoto T . Abnormally high expression of proteasomes in human leukemic cells. Proc Natl Acad Sci U S A. 1990; 87(18):7071-5. PMC: 54685. DOI: 10.1073/pnas.87.18.7071. View

Giurgiu M, Reinhard J, Brauner B, Dunger-Kaltenbach I, Fobo G, Frishman G . CORUM: the comprehensive resource of mammalian protein complexes-2019. Nucleic Acids Res. 2018; 47(D1):D559-D563. PMC: 6323970. DOI: 10.1093/nar/gky973. View

10.

Weber M, Faris R . Subversion of the Endocytic and Secretory Pathways by Bacterial Effector Proteins. Front Cell Dev Biol. 2018; 6:1. PMC: 5787570. DOI: 10.3389/fcell.2018.00001. View

10.

Acosta-Alvear D, Cho M, Wild T, Buchholz T, Lerner A, Simakova O . Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. Elife. 2015; 4:e08153. PMC: 4602331. DOI: 10.7554/eLife.08153. View

11.

Petrocca F, Altschuler G, Tan S, Mendillo M, Yan H, Jerry D . A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells. Cancer Cell. 2013; 24(2):182-96. PMC: 3773329. DOI: 10.1016/j.ccr.2013.07.008. View

12.

Shi C, Kortum K, Zhu Y, Bruins L, Jedlowski P, Votruba P . CRISPR Genome-Wide Screening Identifies Dependence on the Proteasome Subunit PSMC6 for Bortezomib Sensitivity in Multiple Myeloma. Mol Cancer Ther. 2017; 16(12):2862-2870. PMC: 5796678. DOI: 10.1158/1535-7163.MCT-17-0130. View

13.

Kaneko T, Hamazaki J, Iemura S, Sasaki K, Furuyama K, Natsume T . Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell. 2009; 137(5):914-25. DOI: 10.1016/j.cell.2009.05.008. View

14.

Xiao Z, Zhang P, Ma L . The role of deubiquitinases in breast cancer. Cancer Metastasis Rev. 2016; 35(4):589-600. PMC: 5215973. DOI: 10.1007/s10555-016-9640-2. View

15.

Pitcher D, de Mattos-Shipley K, Tzortzis K, Auner H, Karadimitris A, Kleijnen M . Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure. EBioMedicine. 2015; 2(7):642-8. PMC: 4534688. DOI: 10.1016/j.ebiom.2015.05.016. View

16.

. PDBe-KB: a community-driven resource for structural and functional annotations. Nucleic Acids Res. 2019; 48(D1):D344-D353. PMC: 6943075. DOI: 10.1093/nar/gkz853. View

17.

Hornbeck P, Zhang B, Murray B, Kornhauser J, Latham V, Skrzypek E . PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2014; 43(Database issue):D512-20. PMC: 4383998. DOI: 10.1093/nar/gku1267. View

18.

Doncheva N, Assenov Y, Domingues F, Albrecht M . Topological analysis and interactive visualization of biological networks and protein structures. Nat Protoc. 2012; 7(4):670-85. DOI: 10.1038/nprot.2012.004. View

19.

Tsvetkov P, Adler J, Myers N, Biran A, Reuven N, Shaul Y . Oncogenic addiction to high 26S proteasome level. Cell Death Dis. 2018; 9(7):773. PMC: 6039477. DOI: 10.1038/s41419-018-0806-4. View