Traditionally, SWI/SNF chromatin remodelers are associated with increasing chromatin accessibility, INO80 mainly acts as a chromatin repressor, and ISWI and CHD are most often described as histone chaperones in chromatin assembly
[19]. However, these broad classifications are not fixed, as particular chromatin remodelers can be classified into two groups based on the chromatin regions they occupy. BRG1 (SWI/SNF), SNF2H (ISWI), CHD3, and CHD4 proteins are mainly found in active chromatin regions, while BRM (SWI/SNF), INO80, SNF2L (ISWI), CHD1 are associated with inactive chromatin
[20].
2. Alterations of Chromatin Remodeler Complexes in Ovarian Cancer
2.1. ARID1A Alterations in Ovarian Cancer
About 25% of human cancers harbor mutations in at least one of 29 genes encoding SWI/SNF proteins
[41][21]. Among them,
ARID1A (BAF250a, B120, C1orf4, Osa1) is the most frequently altered.
ARID1A mutations are particularly prevalent in gynecologic cancers (found in 10–60% of ovarian and endometrioid carcinoma cases)
[42][22] and pre-malignant gynecological lesions, especially of endometrioid origin
[43][23]. The highest
ARID1A mutation rates are found in ovarian clear cell carcinoma (OCCC) and endometroid ovarian carcinoma suggesting its role in type I OC development and the potential for
ARID1A’s use as a gynecologic cancer biomarker.
None of the previous research found any sufficient correlation between ARID1A protein expression loss and clinical features such as age, FIGO grade, and disease survival
[60][24]. In a subset of microsatellite stable (MSS) endometrial cancer cases, ARID1A’s loss has been associated with a better prognosis and indicated as a potential prognostic biomarker
[61][25]. Further investigation is highly needed to determine ARID1A’s potential as a gynecologic cancer biomarker.
Usually,
ARID1A alterations are loss-of-function mutations such as large deletions, frameshift, or nonsense mutations that lead to the largest BAF complex subunit loss and inactivation of the SWI/SNF complex. However,
ARID1A mutations are not sufficient to promote tumorigenesis alone. Tumors with
ARID1A loss often harbor mutations of the PI3K/AKT pathway, such as inactivating
PTEN or activating
PIK3CA mutations. In mice models, separate
ARID1A or PI3K/AKT pathway mutations promoted ovarian hyperplasia, while concomitant inactivation of
ARID1A together with
PIK3CA activating mutations induced tumors, similar to ovarian clear cell carcinoma (OCCC)
[62][26].
ARID1A downregulation due to inactivating mutations has many downstream effects through epigenetic mark displacement, deregulating gene expression, and reduced protein interactions, primarily affecting DNA damage repair and signaling pathways.
SWI/SNF complex regulates active H3K27ac histone mark at enhancer and promoter regions through interaction with p300/CBR histone acetyltransferase
[63][27]. The acetylation of +1 nucleosome may be required for normal RNA polymerase II (RNAPII) pausing, a crucial step in effective transcription initiation
[64][28]. Thus, ARID1A’s downregulation results in dysregulated expression of at least 99 target genes
[82][29]. The impairment of ARID1A’s function due to inactivating mutations is not fully compensated by its homolog ARID1B. Most notably, one of the affected genes is tumor suppressor
TP53 [64][28].
ARID1A and
TP53 mutations are mutually exclusive in gynecologic malignancies, however, p53 is indirectly regulated by ARID1A. ARID1A is an HDAC6 deacetylase transcriptional repressor. Thus, the loss of ARID1A leads to HDAC6 reactivation, which causes p53 lysine 120 residue deacetylation and apoptosis inhibition
[65][30].
ARID1A’s deficiency has also been linked with telomere impairment. In
ARID1A-deficient cells, topoisomerase II
α(TOP2A) cannot interact with the SWI/SNF ATPase BRG1 (SMARCA4), which it needs to resolve catenanes that develop during replication and transcription
[69][31].
ARID1A’s mutational status in OC cells is also associated with reactive oxygen species (ROS) formation.
ARID1A knockdown in OC cell lines increased intracellular ROS levels, as well as increased oxidative stress marker 8-hydrixyguanosine levels in OCCC patients with low ARID1A expression. Moreover,
ARID1A-mutated cell lines were sensitive to ROS inductor elesclomol
[76][32].
Telomere defects and DNA damage caused by
ARID1A insufficiency leads to increased reliance on double-stranded DNA break (DSB) repair mechanisms
[68][33]. Inactivation or loss of ARID1A or SWI/SNF complexes increases cell sensitivity to cisplatin and UV treatment through the impairment of multiple DSB repair mechanisms
[74][34]. Most notably, ARID1A is involved in HR through DNA end processing (RPA and RAD51 loading), ATR activation, and G2-M cell-cycle arrest maintenance
[72][35]. BAF factors, particularly ARID1A/B, are required for KU70/KU80 protein recruitment to DSB sites during NHEJ
[73][36] as well as XPA accumulation at UV damage sites during NER (nucleotide excision repair)
[74][34].
In ovarian and endometrial cancers,
ARID1A mutations often co-occur with PI3K/AKT pathway gene
KRAS,
PIK3CA, and
PTEN alterations
[77][37]. Additionally, ARID1A’s loss activates the pathway by
ANXA1 (AKT activator) upregulation and
PIK3IP1 (PI3K inhibitor) expression downregulation. In particular,
PIK3IP1 is regulated by ARID1A, suppressing EZH2 methyltransferase that inhibits
PIK3IP1 expression through the H3K27me3 epigenetic mark
[83][38].
Besides its role in SWI/SNF, ARID members have also been reported to co-precipitate with members of E3 ubiquitin ligase. Specifically, ARID1B is linked with elongin C (EloC) through BC box motif and with the addition of cullin 2 and ROC1 form E3 ubiquitin ligase that targets H2B histone explicitly at lysine 120 for monoubiquitination. ARID1B is a paralog that shares most of its sequence with ARID1A. Thus, a similar E3 ubiquitin ligase complex may be formed with ARID1A too. Mutation and depletion of the ARID domain result in decreased ubiquitination of H2B, similar to VHL mutations, causing decreased ubiquitination of HIF1
α in clear cell renal cell carcinoma (ccRCC)
[80][39]. The two genes are often mutated together in ccRCC. The reduced H2B ubiquitination is responsible for reduced H3 histone lysine 79 di-methylation and decreased gene expression
[84][40].
2.2. Other SWI/SNF Alterations in Ovarian Cancer
Although
ARID1A is the most frequently mutated SWI/SNF subunit coding gene, other SWI/SNF members, albeit less often, are also altered in OC. In particular, up to 90% of a rare form of OC, small cell ovarian carcinoma, hypercalcemic type (SCCOHT), a rhabdoid-like tumor has germline or somatic mutations of SWI/SNF ATPase domain BRG1 coding gene
SMARCA4 [90][41]. Just like ARID1A, the SMARCA4 is not only involved in gene expression through the primary SWI/SNF function as chromatin remodeler (
SMARCA4 mutations cause hyperactivation of PRC2 repressive complex)
[43][23], but it also directly participates in DNA repair. BRG1 (SMARCA4) is recruited to DNA damage response (DDR) sites by PARP1 and is activated by deacetylation by SIRT1 to open the affected chromatin region in preparation for HR
[91][42]. Moreover, BRG1 has been associated with
γ-H2AX (a histone mark that indicates damaged DNA) formation, thus likely to promote DSB
[92][43].
Meanwhile, other forms of OC, such as undifferentiated uterine or ovarian carcinoma and OCCC, are found to harbor alterations in other SMARC genes
[93][44]. Most notably, other SMARC gene mutations are found in OCCC:
SMARCA4 in up to 5%,
SMARCA1 at 2%,
SMARCA2 at 1%, and
SMARCC1 at 2%
[94][45]. Although
SMARCA2 mutations are rare, most SCCOHT cases present with dual inactivation of both BGR1 and BRM, though, unlike
SMARCA4,
SMARCA2 is silenced epigenetically
[95][46]. Similar to other rhabdoid tumors, SCCOHT may also harbor SWI/SNF core subunit
SMARCB1 (also known as INI1/SNF5/BAF47) mutations instead of
SMARCA4 [90][41].
2.3. ISWI Alterations in Ovarian Cancer
Similarly, to SWI/SNF, ISWI ATPase domains are also encoded by SMARC genes that frequent alterations in OC. Most notably, ISWI ATPase SNF2L (
SMARCA1) mutations have been linked with OCCC
[94][45]. Although SNF2H is the dominant ISWI ATPase, SNF2L has been described as a regulator of specific gene expression during differentiation. Crucially, SNF2L has been associated with ovarian development and meiotic progression of germ cells during its differentiation
[100][47]. SNF2L interacts with progesterone receptor and steroidogenic acute regulatory protein in ovarian granulosa cells to promote differentiation of the ovary
[101][48].
SMARCA1 deletion has been associated with increased apoptosis through caspase activator Apaf-1 expression upregulation
[102][49] and enhanced proliferation and migration due to WNT signaling regulation in various cancer cells
[103][50].
Depending on which ATPase it binds, ISWI protein remodeling and spacing factor 1 (coded by
RSF1, also known as BAZ1A, HBXAP), forms either RSF-1 or RSF-5 CRC
[27][51]. Immunohistochemical analysis showed that ISWI ATPase SNF2H (
SMARCA5) is overexpressed in OC tissues together with its binding partner RSF1 which is also often upregulated in various tumors, including OC
[104][52]. RSF1 is an essential interphase centromere protein that maintains chromosome stability and protein homeostasis but also has roles in DSB and transcription regulator functions through its interactions with HDAC1, CENP-A, ATM, SNF2H, cyclin E1, CBP, NF-
κB, BubR1, and many other cancer-related proteins
[105][53]. The RSF-1 complex protein expression correlates with cancer stage and poor clinical outcomes in OC patients
[106][54]. The upregulation of RSF-1 and SMARCA5 expression leads to increased double-stranded breaks (DSB) and subsequent DDR
[107][55].
2.4. CHD Family Alterations in Ovarian Cancer
CHD5 is the main CHD family protein linked with cancer [34][56]. Although mutations in the CHD5 gene are detected in OC, CHD5 is also downregulated by increased promoter methylation in OC patient samples [113][57]. In one study analyzing CHD gene promoter methylation in various cancer cell lines, out of all CHD genes, CHD5 promoter was methylated the most often, although the OC cell line (MDAH2774) showed no increase in methylation [114][58]. CHD5 polymorphism (rs9434741) has also been associated with endometriosis, an OC precursor [115][59], however, the clinical significance of this variant is not known. In alignment with CHD5 increased mutation and methylation, CHD5 mRNA expression was found to be downregulated by at least 2-fold in 41% (32/72) of invasive epithelial ovarian carcinomas in comparison with 12 controls and correlated with shorter disease-free survival times [116][60].
2.5. INO80 in Ovarian Cancer
Although several INO80 subunits are overexpressed in melanoma
[122][61], cervical
[123][62], and non-small cell lung cancer
[124][63], according to TCGA data analysis
[125,126][64][65] the only INO80 gene significantly amplified in OC patients is
ACT6LA, shared with SWI/SNF family remodelers.
ACT6LA amplification affects multiple CRCs and causes platinum resistance in OC
[99][66]. However, other INO80 family domains are found to be significantly altered in OC cell models. TRRAP (transformation/transcription domain-associated protein) — a TIP60 remodeler/histone acetyltransferase complex adaptor protein is overexpressed in OC A2780 sphere cultures and was found to govern stemness marker NANOG expression and OC cell proliferation
[127][67]. Yin yang 1 (YY1) — a non-conserved human INO80 family subunit
[38][68] in OC cell line models, has been associated with chemoresistance through upregulation of lncRNA
PART1, which targets
miR-512-3p and causes
CHRAC1 (another CRC gene) upregulation and cisplatin-resistant OC cell proliferation and migration
[111][69]. In OC patients and cell lines YY1 itself was found to be suppressed by
miR-381, which is downregulated in OC tissues
[128][70].