The emerging role of ISWI chromatin remodeling complexes in cancer

Abstract

Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Keywords: Cofactors; ISWI family; Inhibitors; Transcription complexes; Tumor immunology.

Fig. 1

Classification of ISWI family. Molecular components, functional domains, subcellular localization and targeting inhibitors for the ISWI family. A Sixteen different types of ISWI complexes are shown [14, 22, 48]. They harbor either SMARCA1 or SMARCA5 as ATPase subunits and 1–3 noncatalytic subunits. B Schematic representation of functional domains, protein subcellular localization, number of nucleotides and targeting inhibitors for each ISWI protein member

Fig. 2

Gene expression analysis of ISWI family members in human cancers. A Fold changes in gene expression of ISWI members across a variety of tumor types compared to the normal control, based on the TCGA dataset (only tumor types with more than 10 normal samples and tumor samples were selected). FPKM data were used as the expression profile, and the R language limma package was used to conduct variance analysis. Red indicates upregulation, and blue indicates downregulation (P < 0.05 after correction) in tumors. LogFC = log2 (average (tumor)/average (normal)). Full names for cancer abbreviations are shown in the abbreviation table. B A schematic diagram shows the most significant change in the mRNA expression levels of ISWI member genes in different types of cancer based on TCGA dataset analysis or literature summaries. The most significantly upregulated or downregulated genes are marked in red and in blue, respectively

Fig. 3

Representative models of ISWI-IF/cofactor interplay. ISWI family proteins regulate cell phenotypes via association with TF/cofactor, in which the ISWI–TF/cofactor interplay is critical for optimal TF activity. A WASH recruits the NURF complex to the c-Myc promoter through VCA domain-dependent nuclear actin nucleation, which initiates c-Myc expression and maintains the self-renewal and differentiation potential of LT-HSCs [38]. B In liver CSCs. ZIC2 recruits the NURF complex to the OCT4 promoter, accompanied by enrichment of H3K4me3 and increased chromatin accessibility of OCT4, which activates OCT4 transcription and drives the self-renewal of liver CSCs [39]. C BPTF functions as a crucial cofactor of c-MYC required for tumorigenesis. The BPTF requirement for target recognition by c-MYC depends on the epigenetic context: it is dispensable for c-MYC to bind with H3K4me3-rich ‘high-affinity’ promoters and is also necessary for c-MYC to bind with ‘low-affinity’ sequences. BPTF leads to increased c-MYC recruitment to target DNA and regulates chromatin accessibility at c-MYC target promoters, thus increasing c-MYC target gene transcription and driving tumorigenesis [–101]

Fig. 4

ISWI proteins mediate the chemotherapy response and chemical resistance. Some chemotherapy response- and chemoresistance-related genes are regulated by ISWI complexes. The transition of ISWI occupancy by changing DNA methylation levels or targeting ISWI protein/TF interactions may be two treatment strategies for pharmacological intervention. A In AML, the binding of the SMARCA5-CTCF complex at the PU.1 gene is blocked due to DNA methylation. Upon treatment by AZA-mediated DNA demethylation, the SMARCA5-CTCF complex is recruited to the enhancer of the PU.1 gene and inhibits its expression [45]. B The RSF1-SMARCA5 complex functions as a coactivator for NF-κB, consequently augmenting the expression of NF-κB-dependent chemoresistance-related genes, further resulting in paclitaxel resistance in ovarian cancer cells [56]. C Breast cancer cells with estrogen receptor positivity. After EB1089 (vitamin D analog) treatment, the occupancy of vitamin D receptor (VDR) and BAZ1B on CYP19A1 (encoding the enzyme aromatase, which can catalyze the conversion of androgens to estrogens) promoter are altered with the recruitment of VDR and dissociation of BAZ1B, which results in the inhibition of CYP19A1 transcription and contributes to the EB1089 treatment response by arresting the transformation of androgens to estrogens [70, 71]. D In HCC, the recruitment of the NuRD complex by SALL4 to the promoter of some tumor suppressors via an interaction of SALL4 with RBBP4. FFW (a highly potent SALL4-RBBp4 antagonist peptide) treatment abolishes the binding of SALL4 to RBBP4, which leads to the reactivation of tumor suppressors [111]

Fig. 5

ISWI-mediated EMT regulation is critical for tumor progression. ISWI proteins function as cofactors together with specific TFs to modulate EMT-related genes in a context-dependent manner. A In cervical cancer, NKX6.1 directly represses vimentin by interacting with the RBBP7 corepressor, accompanied by an increased H3K27me3 level. Meanwhile, NKX6.1 directly activates E-cadherin by interacting with the BAF155 coactivator with an increased H3K9 acetylation level [105]. B In lung cancer cells, RBBP7 acts as a transcriptional activator of the E-cadherin gene by binding to its promoter region, thereby repressing EMT progression [106]. C Normally, RBBP7, as a corepressor, interacts with HNF1B to repress SLUG transcription and EMT progression. In prostate cancer, upregulation of EZH2 suppresses the levels of the RBBP7/HNF1B transcriptional complex via direct inhibition of HNF1B expression, promoting SLUG transcription and EMT progression [107]. D RBBP7, as a corepressor, suppresses E-cadherin by interacting with TWIST and recruiting the complex to proximal regions of the E-cadherin promoter, thus inducing EMT [108]

Fig. 6

Representative models of ISWI-noncoding RNA interplay in cancer. ISWI family proteins are implicated in the regulation of oncogene transcription involving their interplay with noncoding RNAs. Generally, noncoding RNA recruits ISWI proteins to alter the chromatin environment and histone modification, thereby affecting oncogene transcription. A In gastric tumors, circ-DONSON recruits the SNF2 L-NURF complex to the SOX4 promoter by interacting with SMARCA1, which enriches the transcriptionally active markers H3K27ac and H3K4me3 and increases SOX4 promoter accessibility and transcription [115]. B In colorectal cancer, lncRNA DLEU1 recruits the SNF2 L-NURF complex to the KPNA3 promoter and promotes gene expression through the enrichment of histone modification H3K27ac, which further facilitates malignant behaviors [116]. C LncHOXA10 guides the localization of the SNF2 L-NURF complex to the HOXA10 promoter by directly interacting with SMARCA1, which further activates HOXA10 transcription and promotes liver tumor-initiating cell self-renewal [117]. D lncGata6 recruits the NURF complex to the Ehf promoter and induces gene expression by directly binding with SMARCA1, which further promotes Lgr4/5 (ISC cell-specific marker) expression and activation of Wnt signaling and thus maintains ISC stemness or promotes tumorigenesis [118]

Fig. 7

The mRNA expression levels of ISWI members correlate with immune checkpoint gene levels and immune cell infiltration. The most significant correlation between ISWI members and immune checkpoints at the gene level or between the gene level of ISWI and immune cell infiltration in the 33 tumors from TCGA database are shown in the pie chart. Spearman’s method was used to calculate the correlation between ISWI family members and immune checkpoints (A-C) or immune cell infiltration (D) in 33 tumors. The CIBERSORT algorithm was used to calculate the proportion of different types of cells. Red indicates a positive correlation, blue indicates a negative correlation, and gray indicates no significant correlation. Cancer is abbreviated as follows: Esophageal carcinoma (ESCA), Liver hepatocellular carcinoma (LIHC), Rectum adenocarcinoma (READ), Colon adenocarcinoma (COAD), Lung adenocarcinoma (LUAD), Stomach adenocarcinoma (STAD), Head and Neck squamous cell carcinoma (HNSC), Bladder Urothelial Carcinoma (BLCA), Breast invasive carcinoma (BRCA), Lung squamous cell carcinoma (LUSC), Uterine Corpus Endometrial Carcinoma (UCEC), Kidney renal clear cell carcinoma (KIRC), Thyroid carcinoma (THCA), Kidney Chromophobe (KICH), Kidney renal papillary cell carcinoma (KIRP), Prostate adenocarcinoma (PRAD)