Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

Abstract

Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4—the core component of the nucleosome remodeling and deacetylase (NuRD) complex—may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either ‘deleterious’, ‘probably/possibly damaging’ or as ‘high/medium pathogenic’; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

Advances in Chromodomain Helicase DNA-Binding (CHD) Proteins Regulating Stem Cell Differentiation and Human Diseases

“…CHD4 could recruit inhibitory chromatin remodelers to the DNA damage repair sites and initiate and support the silencing of tumor suppressor gene. Such functions confirm the oncogenic effect of CHD4 ( Chang et al, 2019 ; Novillo et al, 2021 ). In addition, CHD4, as a co-activator of hypoxia-inducible factor (HIF), is upregulated in human breast tumors and is related to the expression of HIF target genes ( Shieh et al, 2020 ; Wang et al, 2020 ).…”

“…CHD4 is closely associated with breast, endometrial, and colorectal cancer ( Novillo et al, 2021 ). As a crucial ingredient in NuRD complex, the upstream regulating effects of CHD4 involves the recruitment of DNA methyl transferase and key transcriptional repressors ( Hata et al, 2019 ; Wang et al, 2020 ).…”

“…In addition, CHD4, as a co-activator of hypoxia-inducible factor (HIF), is upregulated in human breast tumors and is related to the expression of HIF target genes ( Shieh et al, 2020 ; Wang et al, 2020 ). Besides this, CHD4 was associated with poorer overall survival in breast cancer patients ( Novillo et al, 2021 ).…”

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

“…CHD4 shows significantly lower expression in lineage switched AML when compared to ALL presentation and is differentially spliced in the MPAL cases (Figure 3E, 6B). Finally, whilst CHD4 mutations have been reported in <1.5% MLL-germline childhood ALL cases 27 , as with the R1068H mutation found in the relapse of patient LS01, these variants commonly affect highly conserved residues in the helicase/ATPase domains and are predicted to disrupt its activity (Figure 6C,S5C) [28][29][30] . In contrast, recurrent mutations in other NuRD complex members have not been described in ALL and no other NuRD complex member was clonally mutated in our cohort (Table S6).…”

The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families

“…The DNA binding capacity of this domain suggests that it could relieve the C1a-imposed auto-inhibition by interacting with linker DNA, thus activate remodelling. This proposed mechanism could explain the observation of mutations in the 1230–1810 region that are frequently observed in patients with breast cancer 63 or neurodevelopmental disorders 19,63 .…”