Inhibition of MORC2 Mediates HDAC4 to Promote Cellular Senescence through p53/p21 Signaling Axis

Abstract

(1) Background: Colorectal cancer (CRC) is a common gastrointestinal malignancy, accounting for the second largest gastrointestinal tumor. MORC2, a newly discovered chromatin remodeling protein, plays an important role in the biological processes of various cancers. However, the potential mechanistic role of MORC2 in promoting proliferation of CRC carcinoma remains unclear. (2) Methods: The Cancer Genome Atlas database was analyzed using bioinformatics to obtain gene expression and clinical prognosis data. The cell proliferation was assessed by CCK8 and EdU assays, as well as xenograft. SA-beta-gal staining, Western blot, and ELISA assay were using to assess the cell senescence and potential mechanism. (3) Results: Our data showed that MORC2 expression was elevated in CRC patients. Depletion of MORC2 inhibited cellular proliferation both in vivo and in vitro. Further studies showed that the depletion of MORC2 enhanced p21 and p53 expression through decreasing HDAC4 and increasing pro-inflammatory factors IL-6 and IL-8, thus, promoting cellular senescence. (4) Conclusions: We concluded that increased MORC2 expression in CRC might play a critical role in tumorigenesis by regulating the cellular senescence, in addition, MORC2 could be a novel biomarker for clinical outcomes and prognosis and a treatment target for CRC.

Oncogenic MORC2 in cancer development and beyond

“… 26 , 27 , 28 , 78 Aberrant amplification and mutation of MORC2 are frequently shown in human multiple cancers. 24 , 25 , 33 Thus, MORC2 has recently attracted a great deal of attention due to its important role in cancer. The current review analyzed several studies on MORC2 in human cancer and attempted to summarize its precise role in cancer development and treatment.…”

“…Moreover, a recent study found that increased expression of MORC2 promotes tumorigenesis by regulating cellular senescence in CRC. 33 …”

“…Thus, the MORC2-HDAC4 signaling pathway promotes senescence and inhibits CRC proliferation in part by increasing the expression of p21 and p53. 33 …”

Novel Insights into the Role of Chromatin Remodeler MORC2 in Cancer

“…The CDK inhibitor p21 is a crucial regulator of cell survival and proliferation [40]. Zhang et al [41] and Ou, Kepeng et al [42] found that MORC2 expression is inversely correlated with p21 expression in individuals with gastric and colorectal cancers, respectively. Zhang et al also discovered that MORC2 and HDAC1 are recruited onto the p21 promoter to repress its expression in a p53-independent manner.…”

Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies

“…From Drosophila to mammals, Merlin acts as an upstream regulator of the Hippo signaling cascade ( 17 ). Signaling mediated by hepatomegaly (Hippo) is a critical controller of organ size, organogenesis, and stem cell self-renewal ( 18 ). As a result, the Hippo signaling system was newly involved in the process of tumour growth.…”