CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo.

Abstract

The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.

• Authors: Su Jung Oh-Hohenhorst, Derya Tilki, Ann-Kristin Ahlers, Anna Suling, Oliver Hahn, Pierre Tennstedt, Christiane Matuszcak, Hanna Maar, Vera Labitzky, Sandra Hanika, Sarah Starzonek, Simon Baumgart, Steven A Johnsen, Martina Kluth, Hüseyin Sirma, Ronald Simon, Guido Sauter, Hartwig Huland, Udo Schumacher, Tobias Lange
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 29 Issue 1 Pg. 49-61 (01 2022) ISSN: 1476-5500 [Electronic] England
• PMID: 33414516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• DNA-Binding Proteins
• Membrane Proteins
• PMEPA1 protein, human
• Prostate-Specific Antigen
• DNA Helicases
• CHD1 protein, human

Topics

• DNA Helicases (genetics)
• DNA-Binding Proteins (genetics)
• Disease-Free Survival
• Genes, Tumor Suppressor
• Humans
• Male
• Membrane Proteins
• Neoplasm Grading
• Neoplasm Recurrence, Local
• Prostate-Specific Antigen
• Prostatectomy
• Prostatic Neoplasms (genetics, pathology, surgery)