Novel roles of the junctional protein associated with coronary artery disease in regulating Hippo-YAP signalling axis to improve liver regenerative potential

The Hippo/Yap signalling pathway is known to be a conserved pathway that controls organ size by promoting tissue regeneration, however, the mechanism is not fully understood. Emerging experimental research has characterized various roles by which the Hippo mechanism promotes the regenerative capacity of distinct mouse organs such as the intestine, heart and the liver, nevertheless, attempts for therapeutic applications require additional efforts to avoid potential adverse effects. The junctional protein associated with coronary artery disease (JCAD) has been proposed as a new potential therapeutic target in medical conditions, mainly cardiovascular disease. Recently, it has been demonstrated that JCAD negatively regulates Hippo signalling, leading to the activation of YAP (yes-associated protein), the transcriptional effector of the pathway.¹ Zhang and colleagues report novel results of JCAD in regulating liver regeneration in mice subjected to partial hepatectomy (PH) to model patients undergone liver resection or transplanted with small-for-size graft.² Using both global JCAD knockout (JCAD-KO) and conditional JCAD knockout mice, they found decreased expression of genes involved in the cell cycle and impaired DNA replication. Moreover, JCAD deficiency in hepatocytes causes prolongation of the cell cycle due to G2/M transition blockage. When they overexpressed or replenished JCAD in JCAD KO primary hepatocytes, they were able to reverse cell cycle duration, which was abolished by administering the YAP inhibitor, verteporfin. The paper demonstrates that JCAD promotes cycle-dependent hepatocellular regeneration. The dramatic progress being made in the field makes the idea of expanding these findings more tempting. The proposed role of JCAD in liver regeneration opens new avenues for determining potential targets required for therapeutic approaches based on modulation of the cell-cycle machinery.

Previous works of the Hippo/YAP1 pathway have delineated numerous associations of this pathway with human diseases with a wide array of cellular functions.³ An interesting finding is learned from the result that JCAD competed with LATS2 for WWC1 interaction, causing inhibition of LATS2 and YAP activation, and enhanced expression of cell cycle regulatory genes. The mechanistic insights on how cell cycle gene expression integrates with each step of controlling regeneration in the liver will need to be investigated from broader aspects including the development of novel experimental tools required for both the prevention and improvement of different pathologies, with special emphasis on regeneration, transplantation and bioengineering. Sophisticated cell cycle manipulation approaches together with the understanding of how specific genomic regions or configurations respond to cell cycle modulation may precisely control cell fate.

Interestingly, JCAD expression is mainly located in the portal tract cells which suggests an unknown function of JCAD in cholangiocytes that warrants further investigation. An essential task will be to reveal the full range of biological functions of JCAD as well as to perform screens to identify compounds that affect JCAD-Hippo-YaP signaling, versus ones that target other components of the pathway. These possibilities require an in vivo testing of regenerating tissues in mouse models such as those addressing acute or chronic liver injury. These studies would ensure precise JCAD targeting and avoid the occurrence of potential toxicities. To comprehensively understand the pathophysiological function of JCAD in the liver, it is valuable that the JCAD-Hippo-YAP signalling axis is being actively investigated in other liver disorders including liver fibrosis and cholestasis. Taken together, these studies contribute to current research aiming to yield novel therapeutic modalities that impact the liver degeneration process.

The author declares there no competing financial or non-financial interests.

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