Dataset Information

Targeting Lysine-Specific Demethylase 1 (KDM1A/LSD1) Impairs Colorectal Cancer Tumorigenesis by Affecting Cancer Cells Stemness, Motility and Differentiation

ABSTRACT: Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Marcello Manfredi

LAB HEAD: Marcello Manfredi

PROVIDER: PXD037259 | Pride | 2023-07-20

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	CRC_SC1_MGF.zip	Other
	CRC_SC1_WIFF.zip	Other
	CRC_SC1_shA1_2ug_10122020_LIB1.mgf	Mgf
	CRC_SC1_shA2_2ug_10122020_LIB1.mgf	Mgf
	CRC_SC1_shA3_2ug_10122020_LIB1.mgf	Mgf

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Publications

Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation.

Antona Annamaria A Leo Giovanni G Favero Francesco F Varalda Marco M Venetucci Jacopo J Faletti Stefania S Todaro Matilde M Mazzucco Eleonora E Soligo Enrica E Saglietti Chiara C Stassi Giorgio G Manfredi Marcello M Pelicci Giuliana G Corà Davide D Valente Guido G Capello Daniela D

Cell death discovery 20230629 1

Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A also known as LSD1), a FAD-dependent H3K4me1/2 and H3K9me1/2 dem ...[more]

PMID: 37385999

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