LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Ketscher, Anett; Jilg, Cordula A.; Willmann, Dominica; Hummel, Barbara; Imhof, Axel; Rüsseler, Vanessa; Hölz, Stefanie; Metzger, Eric; Müller, Judith; Schüle, Roland

doi:10.1038/oncsis.2014.34

Cited by 57 publications

(45 citation statements)

References 32 publications

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“…PCa cells express several stem cell biomarkers, such as LSD1, SOX2, CD44, and CD133. [28][29][30][31][32] LSD1 and its inhibitor have been reported to target CSC markers in several cancers. 33,34 Sehrawat et al showed that LSD1 promotes PCa cell survival by activating gene networks that regulate the stem cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Piao¹,

Li²,

Feng³

et al. 2020

CMAR

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The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial protein that has been associated with the occurrence and development of malignant tumors. Previous studies have shown that LETM1 expression is increased in several types of human cancer and is associated with a poor clinical outcome. However, the role of LETM1 in prostate cancer (PCa) has not yet been determined. In this study, we investigated the clinicopathological significance of LETM1 expression and its role in PCa progression. Methods: We assessed the expression of LETM1 and genes related to cancer stemness, epithelial-mesenchymal transition (EMT), cell cycle, and PI3K/Akt signaling in 133 paraffinembedded PCa tissue samples and cancer cells by using immunohistochemistry, immunofluorescence, and Western blotting. Results: LETM1 expression was significantly increased in PCa, and it was positively correlated with Gleason score, pathologic tumor (pT) stage, clinical stage, and high microvessel density. Survival analysis showed that patients with PCa with a high level of LETM1 expression exhibited a low overall survival. Cox regression analysis indicated that LETM1 is an independent poor prognostic PCa factor. Additionally, the expression of LETM1 was correlated with cancer cell stemness-associated genes, EMT-related genes, cell cycle regulatory genes, and PI3K/Akt signaling gene expression in PCa. Furthermore, knocking down LETM1 expression down-regulated the expression of stemness-related proteins, while inhibiting tumor spheroid formation, EMT-like changes, cell proliferation, migration, and invasion in PCa cells. Importantly, the PI3K inhibitor LY294002 strongly inhibited the expression of LETM1, pPI3K-p85, and pAkt (Thr308, Ser473) in PCa cells. Conclusion: These results indicate that LETM1 expression is associated with cancer cell stemness, promotes EMT-like changes and cell proliferation and is a potential prognostic biomarker for PCa.

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Section: Discussionmentioning

confidence: 99%

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Piao¹,

Li²,

Feng³

et al. 2020

CMAR

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“…For instance, LSD1 inhibitors have been shown to inhibit the growth of teratocarcinoma, embryonic carcinoma, and seminoma cells (44). On the other hand, LSD1 depletion increased migration and invasion of androgenindependent prostate cancer cells (52). The dichotomy of this "Janus" effect (53) bears relevance given the nonuniform pharmacologic distribution of therapeutic agents within tumors (54,55).…”

Section: Discussionmentioning

confidence: 99%

Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

Kozono

Nitta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.epigenomics | glioblastoma | neoplastic stem cells G lioblastoma is the most common primary brain cancer and remains one of the deadliest of malignancies despite contemporary treatment strategies (1), with near-uniform fatality within 2 y of diagnosis (2, 3). There is growing evidence that the lethality of this tumor is driven by subpopulations of cells with properties of self-renewal and tumorigenicity (4)-that is, the capacity to generate phenocopies of the original tumor when transplanted (5, 6). How glioblastoma cells retain or gain tumorigenicity while the bulk of the tumor does not remains a fundamental question. Conceptualization of this phenomenon includes the elite and stochastic models (7). The elite model states that restricted cell subpopulations harbor intrinsic tumorigenic properties that cannot be acquired once lost. The stochastic model, on the other hand, presupposes that all cells within a population are intrinsically comparable in their ability to spontaneously acquire or lose tumorigenicity.Epigenetic alterations are stable, long-term changes in cellular phenotype that are not due to variations in DNA sequence (8). One means by which epigenetic alterations impact cell phenotype involves modulation of transcriptional activity via histone modification (9). Here we demonstrate that glioblastoma tumorigenicity is best conceptualized by a hybrid elite-stochastic model governed by histone modification through the lysine-specific demethylase 1 (LSD1; aka KDM1A) (10). This modification, in turn, influences the expression of key transcription factors required to reprogram glioblastoma cells into a stem-like state, including avian myelocytomatosis viral oncogene homolog (MYC) (11), oligodendrocyte lineage transcri...

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“…Several factors have been demonstrated to affect AR-mediated transcription such as epigenetic modifications, pioneer factors, and chromatin accessibility 9,12 . Demonstrating the importance of these coactivators and pioneer factors, FOXA1, HOXB13, GATA2, and KDM1A have been shown to be critical for AR signaling and are required for the growth of PCa cell lines [13][14][15][16] . In addition to initiating PCa growth, there is also evidence that AR signaling is associated with DNA damage.…”

mentioning

confidence: 99%

Androgen receptor-binding sites are highly mutated in prostate cancer

et al. 2020

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Androgen receptor (AR) signalling is essential in nearly all prostate cancers. Any alterations to AR-mediated transcription can have a profound effect on carcinogenesis and tumor growth. While mutations of the AR protein have been extensively studied, little is known about those somatic mutations that occur at the non-coding regions where AR binds DNA. Using clinical whole genome sequencing, we show that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor and specific to only prostate cancer. Demonstrating this may be common to lineage-specific transcription factors, estrogen receptor binding sites were also found to have elevated rate of mutations in breast cancer. We provide evidence that these mutations at AR binding sites, and likely other related transcription factors, are caused by faulty repair of abasic sites. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and can impact enhancer activity.

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LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Cited by 57 publications

References 32 publications

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

Androgen receptor-binding sites are highly mutated in prostate cancer

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