Circular RNAs modulate Hippo-YAP signaling: functional mechanisms in cancer

Abstract

The Hippo signaling pathway is an evolutionarily conserved network that regulates organ size and tissue homeostasis in mammals. This pathway controls various cell functions, such as growth, proliferation, survival, apoptosis, and stemness by switching 'on' or 'off' its inhibitory and/or transcriptional module, thereby regulating target gene(s) expression. Altered Hippo signaling has been implicated in various forms of cancers. Increasing evidence suggests cross-talk between the Hippo signaling pathway and non-coding RNAs, in particular circular RNAs (circRNAs). In this context, the current review presents the mechanistic interplay between the Hippo pathway and related circRNAs in various forms of cancers, along with the capabilities of these circRNAs to function either as tumor suppressors or oncogenes through miRNA sponging or protein binding mechanisms. Furthermore, we discuss the constraints and limitations in circRNA mechanistic studies while highlighting some outstanding questions regarding the roles of circRNAs associated with the Hippo-YAP pathway in cancer. Finally, we delineate the potential of these circRNAs to be employed as diagnostic and prognostic biomarkers, as well as molecular hotspots for cancer therapy.

Keywords: Hippo pathway; YAP; cancer progression; circRNA; circular RNA; signal transduction.

Figure 1

Mechanistic details of Hippo-YAP signaling pathway in human cells. (A) If the Hippo pathway is switched off or inactivated, YAP/TAZ remain unphosphorylated and are translocated into the nucleus to bind TEAD group of transcription factors, therefore, regulating the transcription of gene(s) necessitated for cell proliferation and survival. (B) Upon activation of Hippo signaling pathway, numerous biochemical, mechanical and physical cues bring about MST1/2 and LATS1/2 phosphorylation. Phosphorylated LATS1/2 Kinases further phosphorylate YAP/TAZ, therefore, engaging either 14-3-3 or Ubiquitin proteins to mediate YAP/TAZ cytoplasmic retention or ubiquitylation/ proteasomal degradation, respectively.

Figure 2

Diagrammatic illustration of circRNAs regulating the Hippo-YAP signaling pathway. (A) The Hippo pathway is triggered in response to a wide variety of physical, mechanical and biochemical signals, or by FAT family of Cadherins (FAT1-4), thus regulating diverse biological processes and pathological states including cancer. (B) hsa_circ_000585 binds to miR-615-5p and modulates AMOT activity in cholangiosarcoma. (C) circLARP4 and circRNA_0000140 regulate LATS1/2 expression by sponging miR-424-5p and miR-31 in gastric cancer and oral squamous cell carcinoma, respectively. (D) Hsa_circ0091074 controls TAZ activity by forming an endogenous sponge for miR-1297. (E) Hsa_circ_0023404, circPPP1R12A, circRNA_104075, circDDYL, circFAT1, circ0106714, circRNA_000585, and hsa_circ_0005273 act as sponges for miRNAs in cervical cancer, colon cancer, hepatocellular carcinoma, multiple myeloma, osteosarcoma, colorectal cancer, cholangiosarcoma, and breast cancer, respectively. In contrast, circYAP inhibits YAP1 translation through protein binding mechanisms and acts as tumor suppressor in breast and liver cancers. (F) circPVT1 binds to miR-497-5p and alters the activity of the YAP/TEAD complex in head and neck squamous cell carcinoma.

Figure 3

Functional mechanisms of circRNAs modulating the Hippo-YAP signaling pathway in various forms of cancer. This figure illustrates the circRNAs associated with the Hippo-YAP signaling axis in different forms of human cancers. The left column indicates the types of cancer in which these related circRNAs are functionally implicated. The column in the middle depicts the circRNA that has been described to alter YAP1 expression in breast cancer and liver cancer through an efficient protein binding mechanism that halts YAP1 translation. The right column lists those circRNAs that have been observed to act as sponges for miRNA, leading to cancer development and progression.

Figure 4

Potential applications of Hippo-YAP related circRNAs in cancer prognosis/diagnosis and/or therapy. This figure displays the Hippo-YAP associated circRNAs with prognostic/diagnostic and therapeutic significance in different forms of cancers. circRNAs that can potentially be employed as prognostic/diagnostic markers are colored blue and those reported to have possible therapeutic value are colored red. Whereas, circRNAs marked black are indicative of both prognostic and therapeutic significance in respective cancer type. (Where BC = Breast Cancer, HCC = Hepatocellular Carcinoma, GC = Gastric Cancer, OSSC = Oral Squamous Cell Carcinoma, HNSCC = Head and Neck Squamous Cell Carcinoma, CC = Cervical Cancer, CRC = Colorectal Cancer, OS = Osteosarcoma, MM = Multiple Myeloma, and CS = Cholangiosarcoma).