A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth
The hedgehog (Hh) pathway is essential for animal development, but aberrant activation promotes cancer growth. In this study, we show that GIPC3, a PDZ domain-containing protein with putative adaptor protein function, positively modulates Hh target gene expression in normal fibroblasts and melanoma...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2022
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| Online Access: | https://hdl.handle.net/10356/159770 |
| _version_ | 1826113038612168704 |
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| author | Patmanathan, Sathya Narayanan Tong, Bing Teck Teo, Jackie Jia Hao Ting, Jonathan Yong Zheng Tan, Nguan Soon Sim, Kenice Siew Hoon Ta, Yng-Cun Woo, Wei-Meng |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Patmanathan, Sathya Narayanan Tong, Bing Teck Teo, Jackie Jia Hao Ting, Jonathan Yong Zheng Tan, Nguan Soon Sim, Kenice Siew Hoon Ta, Yng-Cun Woo, Wei-Meng |
| author_sort | Patmanathan, Sathya Narayanan |
| collection | NTU |
| description | The hedgehog (Hh) pathway is essential for animal development, but aberrant activation promotes cancer growth. In this study, we show that GIPC3, a PDZ domain-containing protein with putative adaptor protein function, positively modulates Hh target gene expression in normal fibroblasts and melanoma cells and supports melanoma tumor growth. Using overexpression and epistasis studies, we show that Gipc3 potentiates Hh transcriptional output and that it modulates GLI-dependent transcription independently of Sufu. Whereas we find that GIPC3 protein does not interact with Hh pathway components, Ingenuity Pathway Analyses of GIPC3-interacting proteins identified by coimmunoprecipitation and mass spectrometry show an association with cancer pathogenesis. Subsequent interrogation of The Cancer Genome Atlas and the Human Protein Atlas databases reveals GIPC3 upregulation in many cancers. Using expression screens in selected groups of GIPC3-upregulated cancers with reported Hh pathway activation, we find a significant positive correlation of GIPC3 expression with Hh pathway components GLI1, GLI2, and GPR161 in melanoma lines. Consistently, GIPC3 knockdown in melanoma lines significantly reduces GLI1 and GLI2 expression, cell viability, colony formation, and allograft tumor growth. Our findings highlight previously unidentified roles of GIPC3 in potentiating Hh response and melanoma tumorigenesis and suggest that GIPC3 modulation on Hh signaling may be targeted to reduce melanoma growth. |
| first_indexed | 2024-10-01T03:16:39Z |
| format | Journal Article |
| id | ntu-10356/159770 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:16:39Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1597702022-07-01T07:47:14Z A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth Patmanathan, Sathya Narayanan Tong, Bing Teck Teo, Jackie Jia Hao Ting, Jonathan Yong Zheng Tan, Nguan Soon Sim, Kenice Siew Hoon Ta, Yng-Cun Woo, Wei-Meng Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Skin Research Institute of Singapore, A*STAR Singapore Polytechnic Science::Medicine Primary Cilia Molecular-Cloning The hedgehog (Hh) pathway is essential for animal development, but aberrant activation promotes cancer growth. In this study, we show that GIPC3, a PDZ domain-containing protein with putative adaptor protein function, positively modulates Hh target gene expression in normal fibroblasts and melanoma cells and supports melanoma tumor growth. Using overexpression and epistasis studies, we show that Gipc3 potentiates Hh transcriptional output and that it modulates GLI-dependent transcription independently of Sufu. Whereas we find that GIPC3 protein does not interact with Hh pathway components, Ingenuity Pathway Analyses of GIPC3-interacting proteins identified by coimmunoprecipitation and mass spectrometry show an association with cancer pathogenesis. Subsequent interrogation of The Cancer Genome Atlas and the Human Protein Atlas databases reveals GIPC3 upregulation in many cancers. Using expression screens in selected groups of GIPC3-upregulated cancers with reported Hh pathway activation, we find a significant positive correlation of GIPC3 expression with Hh pathway components GLI1, GLI2, and GPR161 in melanoma lines. Consistently, GIPC3 knockdown in melanoma lines significantly reduces GLI1 and GLI2 expression, cell viability, colony formation, and allograft tumor growth. Our findings highlight previously unidentified roles of GIPC3 in potentiating Hh response and melanoma tumorigenesis and suggest that GIPC3 modulation on Hh signaling may be targeted to reduce melanoma growth. Ministry of Education (MOE) Nanyang Technological University This research is supported by a Ministry of Education Research Start-up Funding (Lee Kong Chian School of Medicine, Nanyang Technological University) to WMW and by the Ministry of Education, Singapore, under its Academic Research Fund Tier 1 to WMW (2016-T1-001-130) and to NST (2017-T1-002-103, RG143/17). We acknowledge Nanyang Technological University Undergraduate REsearch on CAmpus consumable fund (to YZJT and JHJT) and Singapore Polytechnic consumable fund (to BTT). 2022-07-01T07:47:14Z 2022-07-01T07:47:14Z 2022 Journal Article Patmanathan, S. N., Tong, B. T., Teo, J. J. H., Ting, J. Y. Z., Tan, N. S., Sim, K. S. H., Ta, Y. & Woo, W. (2022). A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth. Journal of Investigative Dermatology, 142(1), 179-188.e4. https://dx.doi.org/10.1016/j.jid.2021.04.033 0022-202X https://hdl.handle.net/10356/159770 10.1016/j.jid.2021.04.033 34224745 2-s2.0-85114997651 1 142 179 188.e4 en 2016-T1-001-130 2017-T1-002-103 RG143/17 Journal of Investigative Dermatology © 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved. |
| spellingShingle | Science::Medicine Primary Cilia Molecular-Cloning Patmanathan, Sathya Narayanan Tong, Bing Teck Teo, Jackie Jia Hao Ting, Jonathan Yong Zheng Tan, Nguan Soon Sim, Kenice Siew Hoon Ta, Yng-Cun Woo, Wei-Meng A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title | A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title_full | A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title_fullStr | A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title_full_unstemmed | A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title_short | A PDZ protein GIPC3 positively modulates hedgehog signaling and melanoma growth |
| title_sort | pdz protein gipc3 positively modulates hedgehog signaling and melanoma growth |
| topic | Science::Medicine Primary Cilia Molecular-Cloning |
| url | https://hdl.handle.net/10356/159770 |
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