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LOSS OF DKC1 IN CUTANEOUS SQUAMOUS CELL CARCINOMA RESULTS IN A METABOLIC REWIRING AND THE ACQUISITION OF METASTATIC TRAITS LOSS OF DKC1 RESULTS IN THE ACQUISITION OF A LIPIDIC METABOLISM AND METASTATIC TRAITS IN CUTANEOUS SQUAMOUS CELL CARCINOMA OTROS TITULOS

ABSTRACT: Metastaticsis disease remains, by far, the leading cause of all cancer-related deaths, despite being a process highly inefficient. The metastatic process is highly inefficient as the initial dissemination of cancer cells from many primary tumors involves intravasation to lymphatics nodes or blood vessels, a process poorly understood. To investigate generalthe molecular mechanisms involved in this step we analyzed the expression of the epigenetic regulators small non-coding RNAs (sncRNAs) in cutaneous squamous cell carcinoma (cSCC), a highly prevalent malignant tumor that mainly spreads to lymph nodes. Here we report the reduced expression of small nucleolar RNAs (snoRNAs) in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (the protein that stabilizes the snoRNAs) along the metastasis of the carcinomas. DWe demonstrate that depletion of DKC1 in cSCC cells resulted in a switch totriggers lipid metabolism and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial to mesenchymal transition (EMT), suggesting that the rewiring of the lipid metabolism is required to acquire the invasion abilities. Furthermore, the expression of the enzyme HMGCS1 is associated with pathologic features of high metastatic risk in cSCC patients, underpinning the relevance of the mevalonate metabolism in the lymphatic dissemination step.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: guadalupe espadas

LAB HEAD: Eduard Sabidó

PROVIDER: PXD034155 | Pride | 2023-01-31

REPOSITORIES: Pride

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			Action	DRS
	190118_S_IHIH_01_02_2ug.raw	Raw
	190118_S_IHIH_01to02.msf	Msf
	190118_S_IHIH_02_02_2ug.raw	Raw
	190118_S_IHIH_03_02_2ug.raw	Raw
	190118_S_IHIH_04_02_2ug.raw	Raw

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Project description:Background: Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies, with rising incidence rates. There are limited treatment options for advanced and metastatic cSCC and particularly high-risk groups, such as organ transplant recipients, are in urgent need for strategies to treat aggressive cSCC. We have previously developed a preclinical murine model for cSCC, with remarkably similar histopathology and genetics to human cSCC. Understanding the impact of DNA methylation in cSCC may provide avenues to develop new treatment or prevention strategies. Here, we perform reduced-representation bisulfite sequencing based DNA methylation analysis of a murine cSCC model (6 tumors, 6 controls, 2 independent healthy skin samples) and compare results with publicly available human cSCC methylation data for two cSCC subtypes, stem-cell like and keratinocyte like tumors. Results: Contrasting most cancers, general DNA hypermethylation was previously reported for high-risk human cSCC. Similarly, we found significantly increased average methylation in mouse cSCC as well as in stem-cell like, but not keratinocyte like, human cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. One differentially methylated region was located in a potential enhancer of the tumor suppressor gene Filip1l and expression of this gene was significantly reduced in mouse tumors and human cSCC cell lines. Furthermore, comparison of differentially methylated genes revealed remarkable similarities between human and mouse cSCC. Conclusion: Our data suggest that, in addition to mutations, deregulation of DNA methylation is an important feature of murine and human cSCC. DNA methylation likely contributes to silencing of tumor suppressor genes, as shown for the Filip1l gene. The similarities between mouse and human cSCC, particularly stem-cell like, highlight the clinical relevance of our model and presents unique opportunities to identify new treatment strategies.

Dataset Information

LOSS OF DKC1 IN CUTANEOUS SQUAMOUS CELL CARCINOMA RESULTS IN A METABOLIC REWIRING AND THE ACQUISITION OF METASTATIC TRAITS LOSS OF DKC1 RESULTS IN THE ACQUISITION OF A LIPIDIC METABOLISM AND METASTATIC TRAITS IN CUTANEOUS SQUAMOUS CELL CARCINOMA OTROS TITULOS

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