The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2
Year: 2025
Type: article
Abstract: Epigenetic modulators of the histone deacetylase (HDAC) family control key biological processes and are frequently dysregulated in cancer. There is superior activity of HDAC inhibitors (HDACi) in patients with myeloproliferative neoplasms (MPNs) that carry the Janus kinase-2 point mutant JAK2 V617F . This constitutively active tyrosine kinase activates signal-transducer-and-activator-of-transcription (STAT) transcription factors to promote cell proliferation and inflammatory processes. We reveal that the inhibition of HDAC1/HDAC2 with the clinically advanced HDACi romidepsin, the experimental HDACi entinostat and MERCK60, and genetic depletion of HDAC1/HDAC2 induce apoptosis and long-term growth arrest of primary and permanent MPN cells in vitro and in vivo. This treatment spares normal hematopoietic stem cells and does not compromise blood cell differentiation. At the molecular level, HDAC1 and HDAC2 control the protein stability of SIAH2 through acetylation. Genetic knockout experiments show that SIAH2 accelerates the proteasomal degradation of JAK2 V617F in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8. SIAH2 binds to the surface-exposed SIAH degron motif VLP1002 in the catalytic domain of JAK2 V617F . At the functional level, SIAH2 knockout MPN cells are significantly less sensitive to HDACi. Global RNA sequencing verifies that JAK-STAT signaling is a prime target of SIAH2. Moreover, HDAC1 is an adverse prognostic factor in patients with acute myeloid leukemia ( n = 150, p = 0.02), being a possible complication of MPNs. These insights reveal a previously unappreciated link between HDAC1/HDAC2 as key molecular targets, the still undefined regulation of cytoplasmic-to-nuclear signaling by HDACs, and how HDACi kill JAK2 V617F -positive cells from MPN patients and mice with JAK2 V617F in vitro and in vivo.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,790
Awards: G1260688154, G1261213125, Synthese und Pharmakologie neuer Histon DeacetylaseInhibitoren und von Proteolyse vermittelnden Chimären (PROTACs) für mutierte FMSlike TyrosinKinase3, FOR 5659: TARGETMPN: Zielgerichtetes Vorgehen gegen KrankheitsPersistenz und Progression bei myeloproliferativen Neoplasien (MPN), Analyse der neu entdeckten Kontrolle der HSV1 Replikation durch die PP2A BTyp Untereinheit PR130, NGS Sequencer, G300821818, G3146401512, SFB 1361: Regulation von DNAReparatur und Genomstabilität, Molekulares Design, Synthese und Pharmakologie von gezielten Proteinabbauenden Verbindungen für die CheckpointKinase ATR, Analyse der Relevanz der epigenetischen Modulatoren HDAC1, HDAC2 und HDAC3 für die Zytotoxizität und die Induktion von DNASchäden in Tumorzellen bei DNA Replikationsstress, SFB 1292: Gezielte Beeinflussung von konvergierenden Mechanismen ineffizienter Immunität bei Tumorerkrankungen und chronischen Infektionen, G5579344277, Molekulares Design, Synthese und Pharmakologie von neuen und selektiven Histondesacetylase 10 (HDAC10) Inhibitoren, G6145221615, Analyse der neuen HDAC3SIAH2 Signalkaskade und deren Einfluss auf onkogenes JAK2 in Leukämiezellen, Funktionelle Charakterisierung des Kälteschock Proteins Ybx1 als potentielle therapeutische Zielstruktur bei Jak2V617F positiven myeloproliferativen Neoplasien (MPN), G7578079922, G764059879
OpenAlex ID: W4413783946