bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒07‒03
seven papers selected by
Ankita Daiya
BITS Pilani

  1. Expert Opin Ther Pat. 2022 Jun 29.
      INTRODUCTION: The Hippo pathway represents a new opportunity for the treatment of cancer. Overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) or TEAD has been demonstrated in cancers and YAP is known to mediate resistance to cancer drugs. Since 2018, the potential of this pathway has been illustrated by numerous articles and patents and the first drugs entering in clinical trial phase 1.AREAS COVERED: The present review is limited to published patent applications that have disclosed direct small molecule inhibitors of the YAP/TAZ-TEAD interaction.
    EXPERT OPINION: The YAP/TAZ-TEAD transcriptional complex is a promising target for the treatment of cancer. Approximately thirty international patents (used database: Sci-finder, query: TEAD; documents: patents; period: from 2017-January 2022) that disclose TEAD transcriptional inhibitors have been filled since 2018. The mechanism of action is not always described in the patents, we can divide the drugs into three different categories: (i) external TEAD ligands; (ii) non-covalent TEAD ligands of the palmitate pocket; (iii) covalent TEAD ligands which bind into the palmitate pocket. The first molecules in clinical trial phase 1 are non-covalent TEAD ligands although their exact structures is not known. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.
    Keywords:  NF2-deficiency; YAP/TAZ; cancers; hippo pathway; selectivity; transcriptional factors TEAD
  2. Epigenetics Chromatin. 2022 Jun 27. 15(1): 23
      BACKGROUND: Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have discovered that HMGN proteins have important roles in gene regulation and chromatin accessibility, whether and how HMGN proteins affect higher order chromatin status remains unknown.RESULTS: We examined the roles that HMGN1 and HMGN2 proteins play in higher order chromatin structures in three different cell types. We interrogated data generated in situ, using several techniques, including Hi-C, Promoter Capture Hi-C, ChIP-seq, and ChIP-MS. Our results show that HMGN proteins occupy the A compartment in the 3D nucleus space. In particular, HMGN proteins occupy genomic regions involved in cell-type-specific long-range promoter-enhancer interactions. Interestingly, depletion of HMGN proteins in the three different cell types does not cause structural changes in higher order chromatin, i.e., in topologically associated domains (TADs) and in A/B compartment scores. Using ChIP-seq combined with mass spectrometry, we discovered protein partners that are directly associated with or neighbors of HMGNs on nucleosomes.
    CONCLUSIONS: We determined how HMGN chromatin architectural proteins are positioned within a 3D nucleus space, including the identification of their binding partners in mononucleosomes. Our research indicates that HMGN proteins localize to active chromatin compartments but do not have major effects on 3D higher order chromatin structure and that their binding to chromatin is not dependent on specific protein partners.
    Keywords:  Chromatin structure; HMGN; Hi–C; Mass spectrometry
  3. Biochim Biophys Acta Gene Regul Mech. 2022 Jun 23. pii: S1874-9399(22)00055-4. [Epub ahead of print] 194840
      Histone lysine methylation is a post-translational modification that plays a key role in the epigenetic regulation of a broad spectrum of biological processes. Moreover, the dysregulation of histone lysine methyltransferases (KMTs) has been implicated in the pathogenesis of several diseases particularly cancer. Due to their pathobiological importance, KMTs have garnered immense attention over the last decade as attractive therapeutic targets. These endeavors have culminated in tens of chemical probes that have been used to interrogate many aspects of histone lysine methylation. Besides, over a dozen inhibitors have been advanced to clinical trials, including the EZH2 inhibitor tazemetostat approved for the treatment of follicular lymphoma and advanced epithelioid sarcoma. In this Review, we highlight the chemical biology and pharmacology of KMT inhibitors and targeted protein degraders focusing on the clinical development of EZH1/2, DOT1L, Menin-MLL, and WDR5-MLL inhibitors. We also briefly discuss the pharmacologic targeting of other KMTs.
    Keywords:  DOT1L; EZH2; G9a/GLP; Histone Methyltransferase; Menin-MLL; NSD; PRC2; SETD7; SETD8; SUV420H1/2; WDR5-MLL
  4. Cancer Discov. 2022 Jul 01. OF1
      Epigenetic and transcriptional changes support chromatin accessibility alterations and promote a malignant state.
  5. Klin Onkol. 2022 ;35(3): 195-207
      BACKGROUND: A general characteristic of cancer metabolism is the skill to gain the essential nutrients from a relatively poor environment and use them effectively to maintain viability and create new bio-mass. The changes in intracellular and extracellular metabolites that accompany metabolic reprogramming associated with tumor growth subsequently affect gene expression, cell differentiation, and tumor microenvironment. During carcinogenesis, cancer cells face huge selection pressures that force them to constantly optimize dominant metabolic pathways and undergo major metabolic reorganizations. In general, greater flexibility of metabolic pathways increases the ability of tumor cells to satisfy their metabolic needs in a changing environment.PURPOSE: In this review, we discuss the metabolic properties of cancer cells and describe the tumor promoting effect of the transformed metabolism. We assume that changes in metabolism are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.
    Keywords:  Krebs cycle; Metabolism; Warburg effect; anaplerosis; cancer; glutaminolysis; malignancy; oncogenesis; oncometabolite
  6. Biochim Biophys Acta Rev Cancer. 2022 Jun 28. pii: S0304-419X(22)00081-6. [Epub ahead of print] 188756
      The transcriptional regulators YAP and TAZ are involved in numerous physiological processes including organ development, growth, immunity and tissue regeneration. YAP and TAZ dysregulation also contribute to tumorigenesis, thereby making them attractive cancer therapeutic targets. Arbitrarily, YAP and TAZ are often considered as a single protein, and are referred to as YAP/TAZ in most studies. However, increasing experimental evidences documented that YAP and TAZ perform both overlapping and distinct functions in several physiological and pathological processes. In addition to regulating distinct processes, YAP and TAZ are also regulated by distinct upstream cues. The aim of the review is to describe the distinct roles of YAP and TAZ focusing particularly on cancer. Therapeutic strategies targeting either YAP and TAZ proteins or only one of them should be carefully evaluated. Selective targeting of YAP or TAZ may in fact impair different pathways and determine diverse clinical outputs.
    Keywords:  Breast cancer; CRC; Lung cancer; TAZ; Therapy; YAP
  7. Proc Natl Acad Sci U S A. 2022 Jul 12. 119(28): e2200183119
      The term "molecular ZIP (or area) codes" refers to an originally hypothetical system of cell adhesion molecules that would control cell trafficking in the body. Subsequent discovery of the integrins, cadherins, and other cell adhesion molecules confirmed this hypothesis. The recognition system encompassing integrins and their ligands came particularly close to fulfilling the original ZIP code hypothesis, as multiple integrins with closely related specificities mediate cell adhesion by binding to an RGD or related sequence in various extracellular matrix proteins. Diseased tissues have their own molecular addresses that, although not necessarily involved in cell trafficking, can be made use of in targeted drug delivery. This article discusses the molecular basis of ZIP codes and the extensive effort under way to harness them for drug delivery purposes.
    Keywords:  bacteriophage; cancer drugs; integrins; neuropilin; tumor vessels