The Complexity and Dynamics of the Tissue Glycoproteome Associated With Prostate Cancer Progression

Author(s)

Kawahara, Rebeca ^{[1, 2, 3]} ; Recuero, Saulo ^[4] ; Srougi, Miguel ^[4] ; Leite, Katia R. M. ^[4] ; Thaysen-Andersen, Morten ^{[1, 3]} ; Palmisano, Giuseppe ^[2]

Affiliation

^[1] Macquarie Univ, Dept Mol Sci, Sydney, NSW - Australia

^[2] Univ Sao Paulo, Inst Ciencias Biorned, Dept Parasitol, USP, Sao Paulo - Brazil

^[3] Macquarie Univ, Biomol Discovery Res Ctr, Sydney, NSW - Australia

^[4] Fac Med USP, Lab Invest Med Disciplina Urol, Sao Paulo - Brazil

• Document type: Journal article
• Source: MOLECULAR & CELLULAR PROTEOMICS; v. 20, 2021.
• Web of Science Citations: 3

Abstract

The complexity and dynamics of the immensely heterogeneous glycoproteome of the prostate cancer (PCa) tumor microenvironment remain incompletely mapped, a knowledge gap that impedes our molecular-level understanding of the disease. To this end, we have used sensitive glycomics and glycoproteomics to map the protein-, cell-, and tumor grade-specific N- and O-glycosylation in surgically removed PCa tissues spanning five histological grades (n = 10/grade) and tissues from patients with benign prostatic hyperplasia (n = 5). Quantitative glycomics revealed PCa grade-specific alterations of the oligomannosidic-, paucimannosidic-, and branched sialylated complex-type N-glycans, and dynamic remodeling of the sialylated core 1- and core 2-type O-glycome. Deep quantitative glycoproteomics identified similar to 7400 unique N-glycopeptides from 500 N-glycoproteins and similar to 500 unique O-glycopeptides from nearly 200 O-glycoproteins. With reference to a recent Tissue and Blood Atlas, our data indicate that paucimannosidic glycans of the PCa tissues arise mainly from immune cell-derived glycoproteins. Furthermore, the grade-specific PCa glycosylation arises primarily from dynamics in the cellular makeup of the PCa tumor microenvironment across grades involving increased oligomannosylation of prostate-derived glycoproteins and decreased bisecting GlcNAcylation of N-glycans carried by the extracellular matrix proteins. Furthermore, elevated expression of several oligosaccharyltransferase subunits and enhanced N-glycoprotein site occupancy were observed associated with PCa progression. Finally, correlations between the protein-specific glycosylation and PCa progression were observed including increased site-specific core 2-type O-glycosylation of collagen VI. In conclusion, integrated glycomics and glycoproteomics have enabled new insight into the complexity and dynamics of the tissue glyco-proteome associated with PCa progression generating an important resource to explore the underpinning disease mechanisms. (AU)

• FAPESP's process: 14/06863-3 - Post-translational modifications in cancer and parasite infection diagnosis: methodological approaches and biological implications
• Grantee: Giuseppe Palmisano
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 18/18257-1 - Multi-user equipment approved in grant 14/06863-3: HPLC system configured for analysis of carbohydrates, amino acidis, peptides and glycoproteins
• Grantee: Giuseppe Palmisano
• Support type: Multi-user Equipment Program
• FAPESP's process: 15/02866-0 - DISCOVERY AND VERIFICATION OF INTACT GLYCOPEPTIDES AS CANDIDATE PROSTATE CANCER BIOMARKERS USING MASS SPECTROMETRY-BASED PROTEOMICS APPROACHES
• Grantee: Rebeca Kawahara Sakuma
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 18/15549-1 - Post-translational modifications in Chagas Disease biological processes and diagnostics: novel methodological approaches and biological applications
• Grantee: Giuseppe Palmisano
• Support type: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 17/03010-8 - Site-specific characterization of N- and O-linked glycosylation in prostate cancer tissues as molecular signature for disease progression
• Grantee: Rebeca Kawahara Sakuma
• Support type: Scholarships abroad - Research Internship - Post-doctor