Research by the Hong Kong University of Science and Technology (HKUST) has revealed a new mechanism that regulates the secretion of sonic hedgehog (Shh), a key signaling molecule that plays an important role in cancer progression, in mammals, opening the door to new therapeutic strategies for cancer induced by the hedgehog signaling pathway.

The hedgehog (Hh) signaling pathway plays a key role in regulating embryonic patterning and facilitates the development of the central nervous system and organs in the human body. Such a pathway of information transmission between cells is initiated by Hh ligands, which are first secreted by producer cells and then bound to specific receptors on target cells to induce Hh signaling.

Hh signaling is a major target for cancer treatment because this pathway, when hijacked by cancer cells, can promote cancer progression. However, all current Hh antagonists function to inhibit the activity of major factors mediating Hh signaling in target cells, but do not effectively block cancer progression which is promoted by secreted Hh ligands.

Now, an international research team led by Prof. Guo Yusong, Associate Professor in the Division of Life Sciences at HKUST, has revealed the mechanism governing the secretion of sonic hedgehog, a key member of Hh ligands in mammals, from producer cells, offering new insights into inhibiting its secretion and shutting down the Hh signaling pathway when hijacked by cancer cells, thereby preventing cancer progression.

In the conventional secretory transport pathway, newly synthesized secretory proteins are first translocated into the endoplasmic reticulum (ER), where they are folded and modified. These proteins are then packaged into transport vesicles to be delivered to the Golgi apparatus to receive further modifications. Subsequently, they are enriched in transport vesicles at the level of the trans Golgi network (TGN) and delivered to the plasma membrane to be secreted into the extracellular medium.

To study Shh secretion, Professor Guo’s team used a Retention Using Selective Hooks (RUSH) transport assay to analyze sonic hedgehog secretion in a synchronized fashion. Using this and other classical cell and molecular biology approaches, the researchers elucidated that Shh secretion is regulated by the following steps:

1. The SURF4 freight receptor packages Shh into COPII vesicles by directly binding to the CW motif of Shh at the ER.
2. Upon reaching the Golgi, proteoglycans (PGs) compete with SURF4 to bind Shh and promote the dissociation of SURF4 and Shh.
3. The released SURF4 returns to the ER via COPI vesicles.
4. PGs promote TGN-cell surface transport of Shh.

The research results not only reveal a new SURF4-proteoglycan relay mechanism that regulates Shh secretion, but also indicate that blocking the SURF4-Shh interaction is an effective way to inhibit Shh secretion.

This presents the possibility of developing new therapeutic strategies to block cancer progression, in particular ligand-dependent cancer progression mediated by the Hh signaling pathway. »

Teacher. Guo Yusong, Associate Professor of Life Sciences Division at HKUST

The results were recently published in Proceedings of the National Academy of Sciences (PNAS), with a US provisional patent already submitted by the research team for review.

Professor Guo is the corresponding author of the paper, while Professor Elizabeth A. MILLER of MRC Molecular Biology Laboratory, Professor YAO Shuhuai and Professor HUANG Jinqing of HKUST, Professor ZHANG Liang of City University of Hong Kong and Professor HU Junjie from the Chinese Academy of Sciences also participated in this study. Dr. TANG Xiao from HKUST is the first author of this study.