Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer

Besler, Katharina; Weglarz, Aleksandra; Keller, Laura; Amsberg, Gunhild von; Bednarz‐Knoll, Natalia; Offermann, Anne; Stoupiec, Sara; Eltze, Elke; Semjonow, Axel; Boettcher, Lena; Schneegans, Svenja; Perner, Sven; Hauch, Siegfried; Todenhöfer, Tilman; Peine, Sven; Pantel, Klaus; Wikman, Harriet; Werner, Stefan

doi:10.1093/clinchem/hvac073

Cited by 3 publications

(5 citation statements)

References 26 publications

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“…Under androgen deprivation therapy, PC often progresses from the hormone-sensitive (HSPC) to castration-resistant (CRPC) stage and may further transdifferentiate to treatment-resistant variants including tumor lesions with neuroendocrine traits 24 , 25 . Investigating the antagonistic roles of CtBP and RAI2 in PC progression is relevant because both proteins have been shown to be independently involved in PC-associated androgen signaling processes 26 – 28 . To this end, we performed gene expression analyses of circulating tumor cells (CTCs) enriched from blood samples of metastatic PC patients from HSPC, CRPC, aggressive variant PC (AVPC), and histologically evident neuroendocrine prostate cancer (NEPC) 29 , 30 .…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, blood from 10 healthy donors was obtained from the Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, as a negative control. Gene expression in CTCs was analyzed by semiquantitative RT-PCR as described 26 . Briefly, whole blood was incubated with immunomagnetic beads directed against epithelial cell markers, and the enriched cells were washed and lysed.…”

Section: Methodsmentioning

confidence: 99%

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Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

Goradia,

Werner,

Mullapudi

et al. 2024

Nat Commun

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While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

Goradia,

Werner,

Mullapudi

et al. 2024

Nat Commun

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“…The molecular mechanisms involved in these processes are very complex. RAI2, a recently recognized tumour suppressor, is believed to have major parts in the progression and metastasis of quite a few of malignancies including breast cancer [ 8 , 31 ], colorectal cancer [ 7 , 32 ], bladder cancer [ 10 ], and prostate cancer [ 33 ]. However, the specific functions of RAI2 in the proliferation and invasion of GC cells have not been comprehensively investigated.…”

Section: Discussionmentioning

confidence: 99%

RAI2 acts as a tumor suppressor with functional significance in gastric cancer

Lou,

Deng,

Shuai

et al. 2023

Aging

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Metastasis of gastric cancer (GC) is one of the major causes of death among GC patients. GC metastasis involves numerous biological processes, yet the specific molecular biological mechanisms have not been elucidated. Here, we report a novel tumor suppressor, retinoic acid-induced 2 (RAI2), which is located in the Xp22 region of the chromosome and plays a role in inhibiting GC growth and invasion. In this study, integrated analysis of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets and immunohistochemistry staining data suggested that RAI2 expression in GC samples was low. Moreover, the immune infiltration analysis indicated that low expression of RAI2 in GC was associated with a higher intensity of tumor-infiltrating lymphocytes (TILs) and an abundance of Programmed death ligand 1 (PD-L1) expression. Gene set enrichment analysis (GSEA) analysis further revealed that RAI2 regulated some pathways including the GAP junction, focal adhesion and ECM receptor interaction pathway, immune regulation, PI3K-Akt signaling, MAPK signaling, cell cycle, and DNA replication. Furthermore, the knockdown of RAI2 promoted GC cell proliferation, migration, and invasion in vitro . Taken together, these results suggest that the tumor suppressor RAI2 could be a potential target for the development of anti-cancer strategies in GC.

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“…Additionally, blood from 10 healthy donors was obtained from the Institute of Transfusion Medicine, University Medical Center Hamburg Eppendorf, as negative control. Gene expression in CTCs was analyzed by semiquantitative RT-PCR as described 89 . Briefly, whole blood was incubated with immunomagnetic beads directed against epithelial cell markers and the enriched cells were washed and lysed.…”

Section: Methodsmentioning

confidence: 99%

“…CTC gene expression was analyzed as described 92 . Missing values were replaced by ∆Cq max +2 in a gene-specific manner.…”

Section: Gene Expression Analysis In Circulating Tumor Cells (Ctcmentioning

confidence: 99%

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

Goradia

Werner

Mullapudi

et al. 2023

Preprint

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The transcriptional corepressor C-terminal binding proteins (CtBPs) form redox-dependent homo-tetrameric assemblies that regulate the expression of various epithelial, pro-apoptotic and pro-oncogenic genes through their involvement in the multi-component Polycomb repressive complex 2 (PRC2). As CtBPs bind to short linear PxDLS-like sequence motifs, the presence of a tandem ALDLS motif on the putative metastasis suppressor Retinoic acid-induced 2 (RAI2) protein suggested a possible dual, non-canonical interaction with CtBPs. Here, we show that RAI2 induces CtBP polymerization through well-ordered filaments of stacked tetrameric CtBP layers. Consistently, we observed RAI2-mediated CtBP nuclear foci in RAI2-expressing cancer cells. RAI2-mediated CtBP polymerization synchronized with the relief of CtBP-mediated repression of the tumor suppressor gene CDKN1A. Conversely, we found diminishment of RAI2 gene expression during the progression of prostate cancer to treatment-resistant subtypes, concomitant with a marked increase of neuroendocrine markers in a RAI2 depleted prostate cancer cell line. Taken together, our data demonstrate a previously unknown mechanism of multivalent short linear sequence motif-induced polymerization, tipping the balance of opposing oncogenic and tumor suppressive activities. Our findings serve as a model for a broad spectrum of related multivalent protein/protein interactions with diverse functional outcomes and provide a blueprint for the design of tandem motif-based inhibitor compounds targeting oncogenic CtBPs.

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Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer

Cited by 3 publications

References 26 publications

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

RAI2 acts as a tumor suppressor with functional significance in gastric cancer

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

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