Learning from Yeast—How YEATS Domain Proteins Read Epigenetic Marks Driving Oncogenic Programs in Gastrointestinal Tumors

Abstract

YEATS domain-containing proteins (ENL, AF9, YEATS2, YEATS4) have emerged as key chromatin readers that recognize histone acylation marks to regulate transcription, chromatin accessibility, and DNA repair. In their recent review, Fu et al. delineate the diverse oncogenic functions of YEATS paralogs across digestive system malignancies, emphasizing their roles in integrating chromatin dynamics with signaling pathways such as PI3K/AKT, Wnt/β-catenin, HIF1α, and c-Myc. Although the structural features of YEATS domains pose challenges for pharmacological targeting, their consistent involvement in oncogenic transcriptional programs highlights them as promising epigenetic targets. This commentary critically appraises the review’s contribution, highlighting its mechanistic breadth and the implications for targeting YEATS proteins in gastrointestinal tumors.

Digestive system cancers such as hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), gastric cancer (GC), and colorectal cancer (CRC) remain among the gravest challenges in oncology. Despite advances in surgery, cytotoxic chemotherapy, and targeted therapies, survival rates remain poor, since these tumors are often diagnosed when advanced, display profound cellular heterogeneity, and rapidly acquire resistance under therapeutic pressure [1]. Over the past decade, a growing body of work has shifted our understanding of cancer biology, revealing that the epigenome is key to driving malignant behavior. In short, the epigenome regulates how DNA is transcribed, mostly by DNA methylation and via modification of the histones that package DNA and modulate transcription. Chemical modifications of histones include acetylation, crotonylation, benzoylation, and succinylation, collectively termed “marks” that regulate gene expression by directing “reader” proteins, initially discovered in yeast, to interact with diverse expanses of chromatin. Among the many “reader” proteins, the Yaf9, ENL, AF9, Taf14, and Sas5 (YEATS) domain family that includes ENL, AF9, YEATS2, and YEATS4 has emerged as a particularly compelling class of readers that bind these histone acylation marks, translating altered metabolic states into transcriptional programs that fuel proliferation, stemness, survival, and adaptation to stress [2] (Fig. 1). By selectively recognizing acyl-lysine modifications on histone tails, YEATS domain proteins recruit and stabilize chromatin-remodeling complexes and histone acetyltransferases, thereby orchestrating dynamic transcriptional elongation, nucleosome remodeling, and DNA damage repair [3].

Fig. 1.

YEATS domains protein: molecular hubs in digestive cancers. Note: YEATS proteins (YEATS2, YEATS4, AF9, ENL) function as chromatin-associated adaptors that regulate key oncogenic pathways such as WNT/β-catenin, HIF-1α, PI3K/AKT, c-MYC, and NOTCH1. In digestive system tumors, these interactions promote proliferation, therapy resistance, migration, hypoxia, stemness. Their central functions highlight them as promising candidates for targeted therapies

In their comprehensive review recently published in this journal, Fu et al. [2] compellingly highlight the expanded functional landscape of YEATS domain proteins, demonstrating that, beyond their canonical function as epigenetic readers, they also function as key regulators of chromatin architecture and transcriptional dynamics in both physiological and pathological contexts. YEATS domains interact with several key chromatin-associated complexes, including the Super Elongation Complex (SEC), the Ada-two-A-containing (ATAC) histone acetyltransferase complex, the TIP60/p400 chromatin remodeler, and the SRCAP complex. These interactions enable YEATS proteins to interpret a broad spectrum of histone acyl modifications. This capacity for different acyl-mark recognition enables YEATS proteins to modulate transcriptional pause-release, nucleosome remodeling, and DNA damage repair, thereby exerting coordinated and multilayered control over chromatin organization and gene expression [2].

Following primary biochemical characterization of YEATS domains, the review by Fu et al., examines the ubiquity and the context-specific roles of YEATS proteins across gastrointestinal malignancies, integrating evidence derived from HCC, PDAC, GC, and CRC.

The authors start with HCC, a disease often arising from chronic hepatitis and steatosis, characterized by inflammation, hypoxia, and metabolic reprogramming. The readers uncover that YEATS domain proteins have diverse and interconnected oncogenic functions: YEATS4, for example, promotes HCC cell proliferation by stabilizing DDX3 through the upregulation of TCEA1, whereas its interaction with the lncRNA lncAKHE enhances NOTCH2 signaling, further supporting tumor growth and migration. Hypoxic adaptation, a hallmark of HCC, is mediated in part by AF9, which amplifies c-Myc activity via a feedback loop with HIF-1α, reinforcing proliferation under low oxygen. On the metabolic front, AF9 participates in a transcriptional complex with the phosphoglycerate dehydrogenase gene PHGDH, and with p300 and c-Myc to drive CXCL1 and IL-8 expression, fostering immune evasion through neutrophil and TAM recruitment in the liver [4]. Moreover, YEATS2 activates the PI3K–AKT pathway, facilitating survival and invasiveness, while also modulating cellular senescence via both p53/p21 and c-Myc/miR-93-5p axes [5]. These converging functions highlight YEATS proteins as epigenetic conductors orchestrating the interplay between transcription, metabolism, and immune signaling in liver cancer.

The intriguing involvement of YEATS domain protein is also manifest in the complexity of PDAC, a malignancy marked by poor prognosis, dense stroma, and marked drug resistance. The authors highlight how YEATS4 promotes stem-like traits and therapeutic resistance through binding to the histone variant H2A.Z.2 at the NOTCH1 promoter. This epigenetic regulation sustains the expression of NOTCH1, contributing to resistance to gemcitabine, the primary chemotherapeutic agent used in PDAC [6]. At the same time, YEATS2 supports tumor cell survival under inflammatory conditions via the TAK1/NF-κB signaling axis, further illustrating how YEATS readers function as integrators of chromatin state and intracellular signaling [7]. GC and CRC provide additional contexts in which YEATS proteins modulate tumorigenesis. In GC, overexpressed YEATS4 amplifies Wnt/β-catenin signaling by upregulating β-catenin expression, enhancing its phosphorylation and acetylation at target gene promoters, events that drive proliferation and block apoptosis. Notably, suppression of YEATS4 reduces NOTCH2 signaling, activating apoptotic pathways in TP53 wild-type settings, hinting at a possible interplay between p53 status and YEATS dependency [8]. In CRC, ENL localizes to super-enhancers that regulate oncogenes such as c-Myc. Its overexpression correlates with aggressive tumor behavior, whereas its inhibition collapses enhancer architecture and silences transcription of key proliferative drivers [9].

Comprehensively, the review by Fu et al. provides a rigorous and well-structured synthesis of the contributions of YEATS domain-containing proteins to digestive system malignancies, framing these epigenetic readers as dynamic regulators of oncogenic transcriptional networks. By integrating biochemical, structural, and functional studies, the authors delineate how individual YEATS paralogs such as ENL, AF9, YEATS2, and YEATS4 interact with distinct chromatin-associated complexes, converging on key signaling pathways including PI3K/AKT, NOTCH, Wnt/β-catenin, c-Myc and HIF1α [2]. This mechanistic diversity, coupled with functional convergence on essential transcriptional hubs such as c-Myc, supports the view of YEATS domains as central integrators of metabolic and chromatin signals in the regulation of tumor proliferation, plasticity, and survival (Fig. 1).

Although the review outlines strong evidence for the oncogenic relevance of YEATS proteins, it also clarifies that their clinical utility remains to be determined. Their structural features and acyl-lysine recognition present challenges for drug development. Indeed, there is currently a paucity of selective small-molecule inhibitors with efficacy demonstrated in cellular or in vivo models [10]. Moreover, while loss-of-function studies underscore the contribution of specific YEATS paralogs to tumor growth and maintenance, further investigation is required to disentangle their direct oncogenic functions from context-dependent interactions with other chromatin regulators [2]. What emerges from this work is not only a comprehensive cataloging of YEATS-mediated mechanisms, but also a compelling rationale for continued investigation. The identification of recurrent oncogenic circuits modulated by YEATS proteins across different digestive tract cancers suggests that they may represent promising epigenetic targets, although, moving from molecular insight to therapeutic exploitation will require the development of more refined structural tools, functional models, and translational frameworks. In this respect, the review succeeds in both consolidating existing knowledge and highlighting key gaps that will shape the direction of future research (Fig. 1).

Author Contributions

V.C wrote the main manuscript text. G.B reviewed the manuscript.

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Competing interests

The authors declare no competing interests.