Cancer epigenetics

Insulin induces PDHA1 phosphorylation at Ser293, promoting interaction with eEF-1γ and subsequent nuclear translocation. This complex regulates histone acetylation via ACL/p300, modulating RBP4 and EMT marker expression in hepatocellular carcinoma.

Colorectal cancer cell lines accurately recapitulate the histological and transcriptional properties of low-grade and high-grade colorectal cancers.

Five histone marks and transcriptome are profiled for each tumor or non-neoplastic tissue samples to identify genes and regulatory elements involved in non-small cell lung cancer.

Clonal hematopoiesis is associated with an increased risk of hematologic and a range of inflammation-related diseases. Here, Yang et al. demonstrate a critical role for aberrant thrombopoietin receptor signaling in TET2-mutation driven clonal hematopoiesis.

Here, the authors suggest a role of the lysine acetyltransferase KAT7 in inhibiting procentriole formation and colorectal tumorigenesis via competitive antagonism of its crotonylation against acetylation.

Here, the authors characterize the epigenetic status of hybrid ecDNA in HPVOPC, identifying HPV oncogenes E6/E7 in hybrid ecDNA are flanked by somatic DNA enhancers with strong cis-interaction. It can be targeted with ecDNA disrupting therapeutics.

Here, the authors suggest that nitric oxide (NO) is an endogenous epigenetic regulator of gene expression by inhibiting DNA demethylation enzymes (TET and ALKBH2) and increasing DNA methylation at gene regulatory loci throughout the genome.

The oncogene MYC plays a key role in cancer initiation and progression. Using thousands of CRISPR perturbations, the authors investigate regulators of MYC in six different cancers. These tumor-specific regulators suggest potential therapeutic targets for this oncogene.

Copy number alterations occur frequently in patients with triple-negative breast cancer. Here, the authors identify copy number amplification of the role of FAD synthase enzyme (FLAD1) in TNBC and mechanistically demonstrate that this amplification drives tumorigenesis by increasing lipid metabolism via a FLAD1/LSD1/SREBP1 axis.

Metastasis-initiating cells can reawaken from a dormant state that initially allowed them to survive, triggering metastatic outgrowth. Here, authors show that loss of Brd7 promotes an immunosuppressive tumor microenvironment that drives breast cancer metastatic reawakening from dormancy in the lung.

Here, the authors develop a cell-permeable chemical catalyst that acetylates histone H2BK120 in leukemia cells, attenuates NELFE chromatin binding, reprograms transcription, and reduces the tumorigenic potential of leukemia cells in mice.

Super-enhancers (SEs) drive specific gene expression programmes underlying different cancer cell states offering opportunities for therapeutic targeting. Here, the authors suggest targeting SE-dependent genes with synthetic ecteinascidins in tumors with heterogeneous transcriptional landscapes.

ATR inhibitors are being developed for treating cancers, but mechanisms that determine their efficacy are unclear. Here, the authors show that transcription factor KLF5 loss sensitizes cells to ATR inhibition through regulating BRD4 chromatin recruitment. This work also identifies KLF5 as a potential target for treating ARID1A-deficient cancers.

Dissection of the physiological interactomes of histone post-translational modifications is crucial for understanding epigenetic regulatory pathways. Here, authors develop a nucleus-targeting histone-tail-based photoaffinity probe capable of profiling the hPTM-mediated interactomes in native cells.

Glucocorticoid resistance is partly due to epigenetic alterations, but the regulatory mechanisms driving these remain poorly understood. Here, a link between the activity of a lineage-specific transcription factor PU.1 and epigenetic modulators mediating the response to glucocorticoids is described in acute lymphoblastic leukemia.

This study investigates the regulatory mechanisms of DNA-lncRNA triplexes, specifically their role in gastric cancer through the stable formation and precise oncogenic activity of the SENP5/GAU1 triplex. It shows how PPIA orchestrates the SENP5/GAU1 DNA-lncRNA triplex.

X-Ra is a female-specific biomarker from methylation data, linked to defective X-chromosome inactivation. Found in tumors and triple-negative breast cancer, it decreases with chemotherapy. In blood, it associates with cancer, aging, and menopause.

An epigenome-focused CRISPR screen in enzalutamide-resistant prostate cancer identified a unique dependency against SWI/SNF complexes that is potentially mediated by an expansion of their binding regions.

Chromatin and transcriptome studies in myelomonocytic leukemia stem cells revealed repression of retroelements and immune genes. Restoring these pathways by co-inhibiting DNA methylation and H3K9me2 enables selective targeting of leukemic cells.

The molecular mechanisms underlying the late-onset adverse effects of radiotherapy remain to be explored. Here, the authors observe compromised wound healing capacity in irradiated skin from breast cancer survivors and highlight THBS1 as a key epigenetically primed wound repair-related gene.

TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

The role of enhancer-promoter hubs in the regulation of gene expression in cancer remains to be explored. Here, the authors identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia and suggest their potential role in promoting oncogenesis and drug resistance.

ARID1A is a chromatin remodeling protein frequently mutated in cancer. Here the authors report that ARID1A plays a role in forming membraneless organelles through liquid-liquid phase separation (LLPS). ARID1A condensates were elevated in Ewing’s sarcoma patients.

The role of chromatin rewiring of regulatory elements in multiple myeloma (MM) remains poorly understood. Here, the authors identify a super-enhancer driven gene, PPP1R15B whose perturbation confers vulnerability in MM cells and suggest it as a therapeutic target.

The therapeutic options for castration-resistant prostate cancer (CRPC) remain limited. Here, the authors highlight the role of methionine adenosyltransferase 2a (MAT2A) in epigenetic reprogramming and suggest its therapeutic targeting in CRPC.

The role of the histonemethyltransferase KMT2D mutations in head and neck squamous cell carcinoma (HNSCC) remains to be explored. Here, the authors show that KMT2D deficiency in HNSCC impairs the Fanconi Anemia (FA)/BRCA pathway under glycolytic inhibition, rendering HNSCC hypersensitive to DNA crosslinking agents and PARP inhibitors.

A miRNA multi-omics study reveals not only mechanisms for miRNA dysregulation, but also the tumor heterogeneity and immunological diversity within low grade glioma, and presents better prognostic value than traditional molecular markers.

The functional role of transposable elements (TEs) in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors identify a liver-TE/KDM1A/HNF4A regulatory axis that promotes HCC growth and suggest therapeutic targeting of KDM1A.

Leukemias with ambiguous lineage require further characterisation. Here, the authors perform epigenomic and transcriptomic analysis of a subgroup of such leukemias with CpG Island Methylator Phenotype and propose that epigenetic dysregulation and not genetic lesions explains their mixed phenotype.

The success of treatment regimens promoting differentiation has not been explored for all acute myeloid leukemia (AML) subtypes. Here, the authors identify and characterize two lysine (K) deacetylase inhibitors promoting myeloid differentiation in all AML subtypes at low non-cytotoxic doses.

Missense mutations in histones can drive oncogenesis and disrupt chromatin, but the associated mechanisms for many such mutations remain poorly understood. Here, the authors show that cancer-associated histone mutations at arginines in the H3 N-terminal tail disrupt repressive chromatin domains, alter gene expression, and in one case impair differentiation via reduction of PRC2 function.

The role of the FOXA1 to FOXA2 switch in the regulation of the response to androgen receptor signalling inhibition and lineage plasticity in prostate cancer remains unclear. Here, the authors highlight the function of FOXA2 in rewiring AP-1 to induce differential transcriptional reprogramming and lineage plasticity.

Multiomic study reveals that tumor microenvironmental factors such as hypoxia influence intracellular infection of Fusobacterium nucleatum in colorectal cancer cells and provides clues to malignant transformation of infected cells.

Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).

DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.

Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.

The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.

The regulatory landscape of malignant rhabdoid tumor (MRT) due to SMARCB1 loss remains to be explored. Here, the authors perform multi-omics analysis using patient-derived MRT organoids and characterise the epigenetic reprogramming events underlying SMARCB1 loss.

The molecular mechanisms involved in the maintenance of pancreatic cancer stem cells (PCSCs) characteristics are unclear. Here, the authors identify the histone methyltransferase KMT2A as a binding partner of the PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of the PCSCs characteristics and show the therapeutic potential of targeting this axis in pancreatic cancer.

Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.

The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.

The epigenetic mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) are not fully elucidated. Here, the authors reveal a druggable super-enhancer-mediated RNA-binding protein cascade that supports PDAC growth through enhanced mRNA translation.

The functional link between MYC and CTCF in prostate cancer remains to be investigated. Here, the authors highlight the role of MYC in rewiring chromatin architecture by interacting with CTCF protein.

The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.

The suitability of non-invasive surrogate samples for detecting breast cancer remains to be systematically explored. Here, the authors compare non-invasive, non-tumour DNA methylation profiles from cervical, buccal, and blood samples and develop classifiers for breast cancer detection for each sample type.

The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.

Development of targeted MYC inhibitors for cancer therapy remains challenging. Here, the authors design an mRNA medicine which downregulates MYC gene transcription via epigenetic modification of MYC regulatory elements, showing significant antitumor activity in preclinical models of hepatocellular carcinoma.

Somatic structural variants (SVs) in cancer can impact DNA methylation-mediated transcriptional regulation. Here, the authors analyse multi-omics data from over 2400 samples from the Children’s Brain Tumor Network and report SVs that are associated with altered gene expression or DNA methylation, including some with prognostic relevance.

Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.

Class IIA isoform specific inhibition represents an attractive therapeutic target in KMT2A-rearranged infant acute lymphoblastic leukemia.

The relationship between tissue-specific DNA methylation and cancer risk remains to be elucidated. Here, the authors predict DNA methylation at CpG sites for seven cancer types and investigate how these influence cancer risk.

Loss of SMARCB1 has been identified in a number of cancers. Here, the authors report a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers. Simultaneous inhibitors of CBP/p300 could be therapeutic agents for SMARCB1-deficient cancers.

DNA methylation from cell-free DNA (cfDNA) can be profiled using whole genome bisulfite sequencing (WGBS). Here, the authors develop a computational method, FinaleMe, that predicts DNA methylation and tissues of-origin in cfDNA and validate its performance using paired deep and shallow-coverage whole-genome sequencing (WGS) and WGBS data.

Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.

The role of protein arginine methylation in serine metabolism of cancer cells in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors show that phosphoglycerate dehydrogenase (PHGDH) is activated by PRMT1-mediated R236 methylation, promoting serine synthesis, redox homeostasis and HCC growth.

The molecular mechanisms underlying relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) patients remain to be explored. Here, the authors characterise the chromatin accessibility landscape of B-ALL and identify subtype and drug response specific patterns.

Sahm et al. evaluate clinical, imaging, and molecular data from a small cohort of patients with concurrent multiple sclerosis (MS) and gliomas. They report differential methylation of some immune-related loci in tumors from patients with MS, and that inflammatory disease activity can increase in these patients after brain tumor radiotherapy.