Dataset Information

The DNA-helicase HELLS drives ALK^- ALCL proliferation by the transcriptional control of a cytokinesis-related program.

ABSTRACT: Deregulation of chromatin modifiers, including DNA helicases, is emerging as one of the mechanisms underlying the transformation of anaplastic lymphoma kinase negative (ALK^-) anaplastic large cell lymphoma (ALCL). We recently identified the DNA-helicase HELLS as central for proficient ALK^-ALCL proliferation and progression. Here we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and transcriptional cooperators. We demonstrated that HELLS, together with the transcription factor YY1, contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow regulation. Binding target promoters, HELLS primes YY1 recruitment and transcriptional activation of cytoskeleton genes including the small GTPases RhoA and RhoU and their effector kinase Pak2. Single or multiple knockdowns of these genes reveal that RhoA and RhoU mediate HELLS effects on cell proliferation and cell division of ALK^-ALCLs. Collectively, our work demonstrates the transcriptional role of HELLS in orchestrating a complex transcriptional program sustaining neoplastic features of ALK^-ALCL.

SUBMITTER: Tameni A

PROVIDER: S-EPMC7840974 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The DNA-helicase HELLS drives ALK- ALCL proliferation by the transcriptional control of a cytokinesis-related program.

Tameni Annalisa A Sauta Elisabetta E Mularoni Valentina V Torricelli Federica F Manzotti Gloria G Inghirami Giorgio G Bellazzi Riccardo R Fragliasso Valentina V Ciarrocchi Alessia A

Cell death & disease 20210127 1

Deregulation of chromatin modifiers, including DNA helicases, is emerging as one of the mechanisms underlying the transformation of anaplastic lymphoma kinase negative (ALK-) anaplastic large cell lymphoma (ALCL). We recently identified the DNA-helicase HELLS as central for proficient ALK-ALCL proliferation and progression. Here we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and trans ...[more]

PMID: 33504766

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Project description:AimColorectal cancer (CRC) is the fourth most frequently diagnosed cancer worldwide. Despite the decrease in mortality of CRC patients, further investigation of the molecular pathogenesis of CRC could unveil new therapeutic targets and offer better prognosis predictions, which might direct attention to epigenetic regulators.MethodsPublicly available data from the Gene Expression Omnibus (GEO) database and clinical samples were collected. Bioinformatics methods were used to screen hub genes expressed in CRC. qRT-PCR and Western blotting were used to experimentally determine the expression of one gene of interest, the helicase lymphoid-specific (HELLS) gene, at the RNA and protein levels. Immunohistochemical (IHC) assays were used to correlate the stained HELLS proteins to survival data. Cell proliferation levels were assayed by a CCK-8 kit, a colony formation assay was performed, and flow cytometry was used to quantify the cells at each stage of the cell cycle.ResultsA total of 225 overlapping genes were screened, including 14 hub genes. Analysis through a protein-protein interaction (PPI) network and the Gene Ontology database was performed by using the Cytoscape and DAVID online tools, respectively. HELLS RNA and protein expression levels in tumor tissues were 2.09-fold higher and 1.46-fold higher, respectively, than in the peritumoral tissues (p < 0.001, p<0.001). HELLS expression was significantly associated with the T stage (p=0.0027), M stage (p=0.0119), and TNM clinical stage (p = 0.0312) and a higher pathological grade (p=0.049). Highly expressed HELLS was reversibly associated with overall survival (log-rank p = 0.027). HELLS siRNA impaired cell proliferation and colony generation in vitro. HELLS siRNA induced significant G2+M arrest in HT29 and HCT116 cells compared with the respective negative controls (82.29% vs 25.85% and 35.41% vs 15.26%, respectively).ConclusionOur data revealed that HELLS was significantly upregulated in CRC and correlated with clinicopathological parameters. High expression of HELLS indicated poor prognosis for CRC patients. HELLS knockdown led to impaired cell proliferation, colony generation, and G2+M cell cycle arrest.

Dataset Information

The DNA-helicase HELLS drives ALK^- ALCL proliferation by the transcriptional control of a cytokinesis-related program.

Publications

The DNA-helicase HELLS drives ALK<sup>-</sup> ALCL proliferation by the transcriptional control of a cytokinesis-related program.

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