The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective

Abstract

Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.

Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing

“…Multiple pathways enriched for intergenic variants corresponding genes/non-coding RNAs are overlapping with the enriched pathways for genes/non-coding RNAs with variants in intronic, untranslated region (UTR), and non-coding RNA regions, including Axon guidance (FDR = 9.07E-4 & 4.31E-8, respectively), Cell adhesion (FDR = 4.76E-3 & 2.69E-4), Pathways Regulating Hippo Signaling (FDR = 3.74E-4 & 6.52E-10), Splicing factor NOVA regulated synaptic proteins (FDR = 0.003 & 1.56E-6), Hippo-Merlin Signaling Dysregulation (FDR = 0.003 & 1.78E-6), and Ectoderm Differentiation (FDR = 0.008 & 3.8E-5). Genetic variants and observed altered expression of the Hippo pathway have the unique capacity to lead to tumorigenesis and thereby, promote the migration, invasion, and malignancy of cancer cells through cell cycle regulation [20,21]. NOVA factors promote cell proliferation, colony formation, migration, and invasion by interacting with miRNA in cancer cells [22].…”

Comparative transcriptome revealed potential genes related with drug resistance in Melanoma

“…Loss or overactivation of the Hippo pathway may lead to abnormal cell growth and tumorigenesis. In previous studies, researchers found that genes related to the Hippo pathway are often abnormally expressed in various cancers such as liver cancer, colorectal cancer, and lung cancer, and are related to the occurrence and development of tumors (Han, 2019;Xiao and Dong, 2021). The core components of the mammalian Hippo signaling pathway include cytoplasmic kinase module and a nuclear transcriptional module.…”

Oncogenic Pathways in Neurodegenerative Diseases

“…In cancer cells, the aberrant activity of the cell cycle is due to mutations in genes encoding cell cycle proteins or components of upstream signaling pathways. For example, CDKN2A (encodes tumor suppressors p16 INK4A and p14 ARF ) and CDKN2B genes (encodes tumor suppressors p16 INK4A -p14 ARF and p15 INK , respectively) are commonly deleted, or its promoter is silenced by methylation in human cancers [ 210 , 211 ]. Around 54% of glioblastomas present deep deletion of cdkn2a or cdkn2b genes.…”