The DNA-helicase HELLS drives ALK- ALCL proliferation by the transcriptional control of a cytokinesis-related program.
Annalisa TameniElisabetta SautaValentina MularoniFederica TorricelliGloria ManzottiGiorgio InghiramiRiccardo BellazziValentina FragliassoAlessia CiarrocchiPublished in: Cell death & disease (2021)
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.
Keyphrases
- transcription factor
- single cell
- gene expression
- advanced non small cell lung cancer
- dna binding
- genome wide identification
- genome wide
- circulating tumor
- cell proliferation
- single molecule
- cell free
- heat shock
- signaling pathway
- cell therapy
- quality improvement
- diffuse large b cell lymphoma
- stem cells
- tyrosine kinase
- dna damage
- dna methylation
- pi k akt
- protein kinase
- mesenchymal stem cells
- oxidative stress
- dendritic cells
- type iii
- heat stress