The G4 Resolvase DHX36 Possesses a Prognosis Significance and Exerts Tumour Suppressing Function Through Multiple Causal Regulations in Non-Small Cell Lung Cancer

Abstract

Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some cancers such as lung cancer. However, the role of the dominant G4 resolvase DHX36 in the progression of lung cancer remains unknown. In this study, by bioinformatic analysis of public datasets (TCGA and GEO), we find DHX36 is an independent prognosis indicator in non-small-cell lung carcinoma (NSCLC) with subtype dependence. The stable lentiviral knockdown of the DHX36 results in accelerated migration and aggregation of the S-phase subpopulation in lung cancer cells. The reduction of DHX36 level de-sensitises the proliferation response of lung cancer cells to chemotherapeutic drugs such as paclitaxel with cell dependence. The knockdown of this helicase leads to promoted tumour growth, demonstrated by a 3D fluorescence spheroid lung cancer model, and the stimulation of cell colony formation as shown by single-cell cultivation. High throughput proteomic array indicates that DHX36 functions in lung cancer cells through regulating multiple signalling pathways including activation of protein activity, protein autophosphorylation, Fc-receptor signalling pathway, response to peptide hormone and stress-activated protein kinase signalling cascade. A causal transcriptomic analysis suggests that DHX36 is significantly associated with mRNA surveillance, RNA degradation, DNA replication and Myc targets. Therefore, we unveil that DHX36 presents clinical significance and plays a role in tumour suppression in lung cancer, and propose a potentially new concept for an anti-cancer therapy based on helicase-specific targeting.

AP-2δ Is the Most Relevant Target of AP-2 Family-Focused Cancer Therapy and Affects Genome Organization

“…The immunohistochemical data for TRIM22 was additionally included in this step to complement the results of TcoFs analysis—the gene was found to be expressed more abundantly in LUAD than in normal lungs, which could confirm its oncogenic properties in lung cancer [ 70 ]. The other interesting genes are AIFM1 , ATRX, and DHX36, which have not only various IHC data, but also the staining complements literature data on LUAD [ 91 , 95 , 96 ]. In addition, higher cancer-promoting expression is observed in patients with high AP-2δ expression, making TFAP2D a potential oncogene of lung adenocarcinoma.…”

“…On the other hand, BLM or ATRX downregulation is associated with favorable events related to Non-Small Cell Lung Cancer (NSCLC) sensitization to radiotherapy or immunotherapy, respectively [ 94 , 95 ]. Finally, decreased expression of either DHX36 or ERCC3 seems to be unfavorable due to the elevated NSCLC migration and growth [ 96 ] or increased DNA adduct levels [ 97 ], even if the latter one was mainly due to ERCC5 and ERCC6 (in study by Cheng et al, the mean ERCC3 expression was lower in oncological patients but the results were not statistically significant). Additionally, the expression of TFAP2D in both the wild-type and mutated LUAD samples was compared to normal lung samples ( Figure 11 B).…”

Protective effects of Dendrobium huoshanense polysaccharide on D‐gal induced PC12 cells and aging mice, in vitro and in vivo studies

“…Recent studies have shown that the increasing pressure of cell replication causes DNA damage and cell cycle arrest, and replicative senescence is the main cause of body aging (Go et al, 2020; Nechiporuk et al, 2016). Cyclin‐dependent kinases (CDKs) are critical regulators of replicative senescence procession (Cui et al, 2021; Gao et al, 2016; Misono et al, 2019). Furthermore, P21 and P16 are key genes involved in the regulation of CDKs, and their expression levels have been used as important reference indexes in related anti‐aging studies (Chu et al, 2017; Rasool et al, 2017).…”

To unwind the biological knots: The DNA/RNA G‐quadruplex resolvase RHAU (DHX36) in development and disease

“…Likewise, numerous G4 structures found in the human genome and mRNA indicate that G4 and its major resolvase, RHAU, played important roles in regulating gene transcription and translation 51,52 . Previous studies have found that RHAU has an inhibitory effect on the tumorigenesis of lung cancer and breast cancer 53–55 . However, the role of RHAU under these disease conditions remains largely unknown.…”