Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Abstract

Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

Asymmetric Engagement of Dimeric CRL3KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

“…To determine the full repertoire of proteins degraded by UM171, we conducted a global proteomics analysis in two UM171-sensitive leukemia cell lines, SET-2 and MV4;11, after vehicle or UM171 treatment (6 h, 1 µM). LSD1 and two CoREST homologs, RCOR1 (hereafter referred to as CoREST) and HDAC2 partially blocked CoREST-GFP depletion by UM171, likely due to functional redundancy between the two paralogs 26 (Fig. 2a; Extended Data Fig.…”

Paralog-based synthetic lethality: rationales and applications

“…Histone deacetylases (HDACs) alter chromatin structures to modulate transcription levels of nearby genes and lead to the down-regulation of cell cycle regulators and tumor suppressors ( 54 ). Loss of HDAC2 produces SL effects in HDAC1 hemizygous deletion cells ( 26 ). In addition to epigenetic factors, the cohesin complex regulates gene expression by forming a DNA ring, and its members STAG1 and STAG2 have a strong SL interaction ( 27 , 30 , 55 – 57 ).…”

“…For example, in the SWI/SNF complex, the double deletion of ARID1A and ARID1B leads to the structural disruption of the complex ( 19 ), and when both SMARCC1 and SMARCC2 are deleted, the complex is almost completely destabilized ( 43 , 96 ). Additionally, targeting HDAC1/2 in the NuRD complex, can lead to the selective degradation of essential subunits and impair transcriptional control ( 26 ). Another mechanism of SL may arise from altered chromatin interactions, as seen with the single deletion of STAG1 and STAG2, which can alter the distribution of cohesin complexes and cause changes in DNA-DNA loop formation and chromatin accessibility and interactions ( Figure 3A ’) ( 29 , 97 – 99 ).…”

“…Disrupting the stability and/or function of essential proteins by deleting paralogs is an effective mechanism for SL ( Figures 2A and 3B) ( 26 ). An example of paralog-based SL pairs with this mechanism is NXT1-NXT2, which regulates the stability of the essential protein NXF1.…”

“…Some SL pairs could be uncovered using genome-wide single gene perturbation (RNAi or CRISPR) combined with background abnormality in cancer cell lines ( 25 , 26 , 33 , 37 , 42 , 45 , 52 ). However, due to the functional redundancy, it is difficult to directly identify many essential paralogs for given cells.…”