The Hippo Signaling Pathway Manipulates Cellular Senescence

Overview

Journal Cells

Publisher MDPI

Date 2025 Jan 10

PMID 39791714

Authors

Chiharu Miyajima

Mai Nagasaka

Hiromasa Aoki

Kohki Toriuchi

Shogo Yamanaka

Sakura Hashiguchi

Daisuke Morishita

Mineyoshi Aoyama

Hidetoshi Hayashi

Yasumichi Inoue

Affiliations

Soon will be listed here.

Abstract

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation.

References

Sera Y, Nakata Y, Ueda T, Yamasaki N, Koide S, Kobayashi H . UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes. Blood. 2020; 137(7):908-922. PMC: 7918186. DOI: 10.1182/blood.2019001044. View

Price J, Waters J, Darrah C, Pennington C, Edwards D, Donell S . The role of chondrocyte senescence in osteoarthritis. Aging Cell. 2003; 1(1):57-65. DOI: 10.1046/j.1474-9728.2002.00008.x. View

Minagawa S, Araya J, Numata T, Nojiri S, Hara H, Yumino Y . Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011; 300(3):L391-401. PMC: 3284316. DOI: 10.1152/ajplung.00097.2010. View

Debacq-Chainiaux F, Borlon C, Pascal T, Royer V, Eliaers F, Ninane N . Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF-beta1 signaling pathway. J Cell Sci. 2005; 118(Pt 4):743-58. DOI: 10.1242/jcs.01651. View

Farr J, Fraser D, Wang H, Jaehn K, Ogrodnik M, Weivoda M . Identification of Senescent Cells in the Bone Microenvironment. J Bone Miner Res. 2016; 31(11):1920-1929. PMC: 5289710. DOI: 10.1002/jbmr.2892. View

Udan R, Kango-Singh M, Nolo R, Tao C, Halder G . Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003; 5(10):914-20. DOI: 10.1038/ncb1050. View

Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N . FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem. 2002; 277(30):26729-32. DOI: 10.1074/jbc.C200256200. View

Barry E, Simov V, Valtingojer I, Venier O . Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine. Cells. 2021; 10(10). PMC: 8534579. DOI: 10.3390/cells10102715. View

Laberge R, Sun Y, Orjalo A, Patil C, Freund A, Zhou L . MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17(8):1049-61. PMC: 4691706. DOI: 10.1038/ncb3195. View

10.

Matsushita A, Sato T, Mukai S, Fujishita T, Mishiro-Sato E, Okuda M . TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation. Oncogene. 2018; 38(11):1966-1978. DOI: 10.1038/s41388-018-0417-7. View

11.

Xu S, Yuan Z, Jiang C, Chen W, Li Q, Chen T . DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis. Adv Sci (Weinh). 2024; 11(16):e2308531. PMC: 11040361. DOI: 10.1002/advs.202308531. View

12.

Schutte U, Bisht S, Heukamp L, Kebschull M, Florin A, Haarmann J . Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma. Transl Oncol. 2014; 7(2):309-21. PMC: 4101344. DOI: 10.1016/j.tranon.2014.02.005. View

13.

Li H, Li Q, Dang K, Ma S, Cotton J, Yang S . YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression. Cell Rep. 2019; 29(10):3200-3211.e4. PMC: 7871510. DOI: 10.1016/j.celrep.2019.03.021. View

14.

Marion R, Strati K, Li H, Murga M, Blanco R, Ortega S . A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009; 460(7259):1149-53. PMC: 3624089. DOI: 10.1038/nature08287. View

15.

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B . Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015; 17(9):1218-27. PMC: 6186417. DOI: 10.1038/ncb3216. View

16.

Yu T, Ji J, Guo Y . MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells. Biochem Biophys Res Commun. 2013; 441(1):53-8. DOI: 10.1016/j.bbrc.2013.10.008. View

17.

Yamaguchi Y, Madhyastha H, Madhyastha R, Choijookhuu N, Hishikawa Y, Pengjam Y . Arsenic acid inhibits proliferation of skin fibroblasts, and increases cellular senescence through ROS mediated MST1-FOXO signaling pathway. J Toxicol Sci. 2016; 41(1):105-13. DOI: 10.2131/jts.41.105. View

18.

Tufail M, Huang Y, Hu J, Liang J, He C, Wan W . Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants. Aging Dis. 2024; . DOI: 10.14336/AD.2024.0421. View

19.

Davaapil H, Brockes J, Yun M . Conserved and novel functions of programmed cellular senescence during vertebrate development. Development. 2016; 144(1):106-114. PMC: 5278627. DOI: 10.1242/dev.138222. View

20.

Gersey Z, Rodriguez G, Barbarite E, Sanchez A, Walters W, Ohaeto K . Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer. 2017; 17(1):99. PMC: 5292151. DOI: 10.1186/s12885-017-3058-2. View