Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • G quadruplex structures can be resolved

    2022-08-16

    G-quadruplex structures can be resolved by helicases. Consistently, many helicases are aberrantly expressed in cancer TNP-470 [47]. In this study, we correlated HOXC10 expression with that of all helicases using a microarray dataset derived from 759 breast cancer patients [36] and discovered that CHD7 showed the largest correlation coefficient with HOXC10 expression. We noticed that a correlation coefficient of about 0.2 does not suggest a strong correlation. It is likely that other mechanisms also contribute to HOXC10 expression. Nevertheless, when two shRNAs targeting different sites were used to knock down CHD7, we observed reduced Gluc activity in reporter assays and decreased mRNA levels of endogenous HOXC10, implicating that CHD7 may unwind the G-quadruplex structures in the HOXC10 promoter to enhance its expression. As a chromatin remodeling protein, CHD7 controls chromatin structure and thus modulates gene expression. Very few reports have been published regarding the role of CHD7 in cancer development. One previous study indicated that CHD7 levels negatively correlated with recurrence-free survival and overall survival of pancreatic patients [48]. Our study revealed a new mechanism mediated by CHD7 for its role in promoting HOXC10 expression and contribute to mammary oncogenesis. The following is the supplementary data related to this article.
    Conflict of interest
    Transparency document
    Acknowledgement This work was supported by the National Natural Science Foundation of China (81472635, 81672795 and 81872293) and the National Natural Science Foundation of Heilongjiang, China (ZD2015004) to GS. We thank Dr. Daniel Stovall for critically reading our manuscript.
    Introduction G-quadruplexes (G4s) are secondary structures which occur in both DNA and RNA under physiologically relevant conditions [2]. G4s contain 2 or more stacks of 4 coplanar guanine residues stabilized via Hoogsteen hydrogen bonding. The stacking interaction is also facilitated by monovalent cations, such as sodium and potassium, as well as π-stacking of the purine bases (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, Fig. 13, Fig. 14, Fig. 15) [3]. Although it is unclear what promotes G4 formation in vivo, they are increasingly implicated in important biological events such as telomere maintenance, transcription regulation, mRNA translation, and replication [2,[4], [5], [6], [7], [8], [9]]. More recently, chromatin immunoprecipitation and high through-put sequencing analyses have provided in vivo evidence for the presence of ∼9000 non-telomeric G-quadruplexes that reside in nucleosome-depleted promoter regions, confirming many of the previously proposed regulatory G4s [10,11]. Thus, G-quadruplexes appear to be excellent targets for anti-cancer therapeutics [7]. Currently there are greater than 1000 characterized G-quadruplex stabilizing ligands which have been discovered through virtual screening (VS), traditional high-throughput screening (HTS), and plenty of serendipity (see: http://g4ldb.org/for a listing of many verified G4 ligands). Although many of these compounds (TMPyP4, pyridostatin, telomestatin, BRACO-19, etc.) bind with high affinity to G4s, it is often by an end-pasting mechanism and, therefore, non-specific. Furthermore, these compounds commonly do not possess drug-like properties, e.g. they do not pass Lipinski's rule of five [12], nor do they have documented ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles [13]. Extensive work has gone into modifying general end-pasting drug scaffolds such as porphyrins [[14], [15], [16], [17]], phenanthrolines [[18], [19], [20], [21]], anthracenes [22,23], naphthalenes [24], and quinolones [25,26] (Fig. 2A–E). Only Quarfloxin (CX-3543) (Fig. 3A), an end-paster, has progressed to clinical trials [27]. Alternative G4 drug discovery strategies have focused on developing ligands that target the loops and grooves. An example groove-binding ligand is distamycin A (Fig. 3B) which was shown by Randazzo et al. to interact with the grooves of the parallel tetramolecular quadruplex [d (TGGGGT)4] by 1H NMR (proton nuclear magnetic resonance spectroscopy) studies [28,29]. Unfortunately, most G4 groove-binding ligands have poor selectivity over dsDNA (double-stranded DNA), which was the case for distamycin A and netropsin [30] (Fig. 3C). To address this selectivity problem, many researchers have turned to VS drug discovery methods.