UBR7 in concert with EZH2 inhibits the TGF-ß signaling leading to extracellular matrix remodeling.

The intricate interplay between resident cells and the extracellular matrix (ECM) profoundly influences cancer progression. In triple-negative breast cancer (TNBC), ECM architecture evolves due to the enrichment of lysyl oxidase, fibronectin, and collagen, promoting distant metastasis. Here we uncover a pivotal transcription regulatory mechanism involving the epigenetic regulator UBR7 and histone methyltransferase EZH2 in regulating transforming growth factor (TGF)-ß/Smad signaling, affecting the expression of ECM genes. UBR7 loss leads to a dramatic reduction in facultative heterochromatin mark H3K27me3, activating ECM genes. UBR7 plays a crucial role in matrix deposition in adherent cancer cells and spheroids, altering collagen content and lysyl oxidase activity, directly affecting matrix stiffness and invasiveness. These findings are further validated in vivo in mice models and TNBC patients, where reduced UBR7 levels are accompanied by increased ECM component expression and activity, leading to fibrosis-mediated matrix stiffness. Thus, UBR7 is a master regulator of matrix stiffening, influencing the metastatic potential of TNBC.

ZMYND8 Is a Regulator of Sonic Hedgehog Signaling in ATRA-Mediated Differentiation of Neuroblastoma Cells.

Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8) is a crucial epigenetic regulator that plays a multifaceted role in governing a spectrum of vital cellular processes, encompassing proliferation, apoptosis, migration, tumor suppression, and differentiation. It has emerged as a key player in neuronal differentiation by orchestrating the expression of neuronal lineage-committed genes. The present study uncovers the role of ZMYND8 in regulating the Sonic Hedgehog (SHH) signaling axis, which is crucial for neuronal differentiation. Genetic deletion of ZMYND8 leads to a significant reduction in SHH pathway genes, GLI1, and PTCH1 expression during all-trans-retinoic acid (ATRA)-induced differentiation. ZMYND8 and RNA pol II S5P are found to co-occupy the GLI1 and PTCH1 gene promoters, positively impacting their gene transcription upon ATRA treatment. Interestingly, ZMYND8 is found to counteract the inhibitory effects of Cyclopamine that block the upstream SHH pathway protein SMO, resulting in enhanced neurite formation in neuroblastoma cells following their treatment with ATRA. These results indicate that ZMYND8 is an epigenetic regulator of the SHH signaling pathway and has tremendous therapeutic potential in ATRA-mediated differentiation of neuroblastoma.

To Ub or not to Ub: The epic dilemma of histones that regulate gene expression and epigenetic cross-talk.

A dynamic array of histone post-translational modifications (PTMs) regulate diverse cellular processes in the eukaryotic chromatin. Among them, histone ubiquitination is particularly complex as it alters nucleosome surface area fostering intricate cross-talk with other chromatin modifications. Ubiquitin signaling profoundly impacts DNA replication, repair, and transcription. Histones can undergo varied extent of ubiquitination such as mono, multi-mono, and polyubiquitination, which brings about distinct cellular fates. Mechanistic studies of the ubiquitin landscape in chromatin have unveiled a fascinating tapestry of events that orchestrate gene regulation. In this review, we summarize the key contributors involved in mediating different histone ubiquitination and deubiquitination events, and discuss their mechanism which impacts cell transcriptional identity and DNA damage response. We also focus on the proteins bearing epigenetic reader modules critical in discerning site-specific histone ubiquitination, pivotal for establishing complex epigenetic crosstalk. Moreover, we highlight the role of histone ubiquitination in different human diseases including neurodevelopmental disorders and cancer. Overall the review elucidates the intricate orchestration of histone ubiquitination impacting diverse cellular functions and disease pathogenesis, and provides insights into the current challenges of targeting them for therapeutic interventions.

Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy.

T cells, a key component of cancer immunotherapy, undergo a variety of histone modifications and DNA methylation changes since their bone marrow progenitor stages before developing into CD8+ and CD4+ T cells. These T cell types can be categorized into distinct subtypes based on their functionality and properties, such as cytotoxic T cells (Tc), helper T cells (Th), and regulatory T cells (Treg) as subtypes for CD8+ and CD4+ T cells. Among these, the CD4+ CD25+ Tregs potentially contribute to cancer development and progression by lowering T effector (Teff) cell activity under the influence of the tumor microenvironment (TME). This contributes to the development of therapeutic resistance in patients with cancer. Subsequently, these individuals become resistant to monoclonal antibody therapy as well as clinically established immunotherapies. In this review, we delineate the different epigenetic mechanisms in cancer immune response and its involvement in therapeutic resistance. Furthermore, the possibility of epi-immunotherapeutic methods based on histone deacetylase inhibitors and histone methyltransferase inhibitors are under investigation. In this review we highlight EZH2 as the principal driver of cancer cell immunoediting and an immune escape regulator. We have addressed in detail how understanding T cell epigenetic regulation might bring unique inventive strategies to overcome drug resistance and increase the efficacy of cancer immunotherapy.

Lnc-ing epigenetic mechanisms with autophagy and cancer drug resistance.

Long noncoding RNAs (lncRNAs) comprise a diverse class of RNA molecules that regulate various physiological processes and have been reported to be involved in several human pathologies ranging from neurodegenerative disease to cancer. Therapeutic resistance is a major hurdle for cancer treatment. Over the past decade, several studies has emerged on the role of lncRNAs in cancer drug resistance and many trials have been conducted employing them. LncRNAs also regulate different cell death pathways thereby maintaining a fine balance of cell survival and death. Autophagy is a complex cell-killing mechanism that has both cytoprotective and cytotoxic roles. Similarly, autophagy can lead to the induction of both chemosensitization and chemoresistance in cancer cells upon therapeutic intervention. Recently the role of lncRNAs in the regulation of autophagy has also surfaced. Thus, lncRNAs can be used in cancer therapeutics to alleviate the challenges of chemoresistance by targeting the autophagosomal axis. In this chapter, we discuss about the role of lncRNAs in autophagy-mediated cancer drug resistance and its implication in targeted cancer therapy.