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Review
. 2023 Jun;42(2):409-425.
doi: 10.1007/s10555-023-10104-3. Epub 2023 May 6.

Oncogenic signaling-mediated regulation of chromatin during tumorigenesis

Jahangir Alam #  1 , Md Nazmul Huda #  1 , Alan J Tackett  1   2 , Sayem Miah  3   4
Affiliations
Review

Oncogenic signaling-mediated regulation of chromatin during tumorigenesis

Jahangir Alam et al. Cancer Metastasis Rev. 2023 Jun.

Abstract

Signaling pathways play critical roles in executing and controlling important biological processes within cells. Cells/organisms trigger appropriate signal transduction pathways in order to turn on or off intracellular gene expression in response to environmental stimuli. An orchestrated regulation of different signaling pathways across different organs and tissues is the basis of many important biological functions. Presumably, any malfunctions or dysregulation of these signaling pathways contribute to the pathogenesis of disease, particularly cancer. In this review, we discuss how the dysregulation of signaling pathways (TGF-β signaling, Hippo signaling, Wnt signaling, Notch signaling, and PI3K-AKT signaling) modulates chromatin modifications to regulate the epigenome, thereby contributing to tumorigenesis and metastasis.

Keywords: Carcinogenesis and metastasis; Epigenetics; Signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Model for histone modifications and functional consequences. Histone modifications alter the conformation of chromatin structure by either condensing the chromatin and inhibiting transcription (heterochromatin) or relaxing the chromatin and allowing transcription (euchromatin)
Fig. 2
Fig. 2
Canonical TGF-β/SMAD signaling and chromatin regulation. The downstream effectors of TGF-β/SMAD signaling—SMAD2, SMAD3, and SMAD4—take part in chromatin regulation and gene expression by interacting with chromatin-remodeler complexes and associated proteins. The dotted lines indicate further experimental validation is required
Fig. 3
Fig. 3
Schematic of the Hippo signaling pathway in the regulation of chromatin remodeler complexes. Several upstream stimuli/signals can activate Hippo signaling through the phosphorylation of MST1/MST2 and subsequent phosphorylation of LATS1/LATS2 kinases leading to YAP/TAZ phosphorylation resulting in proteasomal degradation or cytoplasmic retention of YAP/TAZ via 14–3-3 protein. Additionally, Neurofibromatosis 2 (NF2) along with MAP4k and TAOK can also activate Hippo signaling without MST1/MST2 phosphorylation. However, when the Hippo pathway is off, YAP/TAZ will not be phosphorylated, thus, nonphosphorylated YAP/TAZ translocates into the nucleus and form complexes with transcription factors, co-activators as well as different chromatic remodeler complexes to facilitate the transcription target genes. Dotted lines indicate upstream signals
Fig. 4
Fig. 4
Activation of Wnt signaling pathway promotes β-Catenin–mediated chromatin regulation. In the absence of Wnt ligands, activated wnt-destruction-complex phosphorylates β-Catenin and promotes ubiquitin-mediated proteolysis of β-Catenin. However, wnt-ligands dependent activation inhibits wnt-destruction-complex, resulting in the stabilization of β-Catenin. The stabilized β-Catenin translocates into the nucleus and the accumulation of nuclear β-Catenin facilitates the transcription of its target genes in association with several chromatin remodeler complexes. The dotted lines indicate further experimental validation is required
Fig. 5
Fig. 5
Notch signaling pathway in chromatin regulation. The binding of the notch-ligand from the signaling cells to the notch-receptor of signal-receiving cells promotes the proteolytic cleavages of the notch-receptor. Metalloprotease ADAM10 catalyzes the S2 cleavage followed by γ-secretase dependent catalysis of S3 cleavage, resulting in release of the Notch intracellular domain (NICD). Released NICD translocates into the nucleus, where it interacts with the co-activators and DNA-binding proteins and chromatin modifying complexes for regulating transcription
Fig. 6
Fig. 6
PI3K/AKT signaling dependent epigenetic regulation. In response to extracellular stimuli, membrane-bound receptor RTKs/GPCRs gets activated leading to phosphorylation of PI3K which catalyzes the phosphorylation of PIP2 to produce PIP3 resulting in the activation of Akt. Activated AKT phosphorylates a variety of substrates, including chromatin remodeler complexes, to regulate epigenetic gene regulation
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