Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells

Antonios D Konitsiotis; Shu-Chun Chang; Biljana Jovanović; Paulina Ciepla; Naoko Masumoto; Christopher P Palmer; Edward W Tate; John Robert Couchman; Anthony I Magee

doi:10.1371/journal.pone.0089899

Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells

Antonios D Konitsiotis, Shu-Chun Chang, Biljana Jovanović, Paulina Ciepla, Naoko Masumoto, Christopher P Palmer, Edward W Tate, John Robert Couchman, Anthony I Magee

Nutritional Immunology

27 Citations (Scopus)

Abstract

Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers. To be highly active, Hedgehog proteins must be palmitoylated at their N-terminus by the MBOAT family multispanning membrane enzyme Hedgehog acyltransferase (Hhat). In a pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and transfected HEK293a cells Hhat localized to the endoplasmic reticulum. siRNA knockdown showed that Hhat is required for Sonic hedgehog (Shh) palmitoylation, for its assembly into high molecular weight extracellular complexes and for functional activity. Hhat knockdown inhibited Hh autocrine and juxtacrine signaling, and inhibited PDAC cell growth and invasiveness in vitro. In addition, Hhat knockdown in a HEK293a cell line constitutively expressing Shh and A549 human non-small cell lung cancer cells inhibited their ability to signal in a juxtacrine/paracrine fashion to the reporter cell lines C3H10T1/2 and Shh-Light2. Our data identify Hhat as a key player in Hh-dependent signaling and tumour cell transformed behaviour.

Original language	English
Article number	e89899
Journal	PloS one
Volume	9
Issue number	3
Pages (from-to)	1-13
Number of pages	13
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0089899
Publication status	Published - 7 Mar 2014

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Konitsiotis, A. D., Chang, S.-C., Jovanović, B., Ciepla, P., Masumoto, N., Palmer, C. P., Tate, E. W., Couchman, J. R., & Magee, A. I. (2014). Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells. PloS one, 9(3), 1-13. Article e89899. https://doi.org/10.1371/journal.pone.0089899

Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells. / Konitsiotis, Antonios D; Chang, Shu-Chun; Jovanović, Biljana et al.
In: PloS one, Vol. 9, No. 3, e89899, 07.03.2014, p. 1-13.

Research output: Contribution to journal › Journal article › Research › peer-review

Konitsiotis, AD, Chang, S-C, Jovanović, B, Ciepla, P, Masumoto, N, Palmer, CP, Tate, EW, Couchman, JR & Magee, AI 2014, 'Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells', PloS one, vol. 9, no. 3, e89899, pp. 1-13. https://doi.org/10.1371/journal.pone.0089899

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abstract = "Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers. To be highly active, Hedgehog proteins must be palmitoylated at their N-terminus by the MBOAT family multispanning membrane enzyme Hedgehog acyltransferase (Hhat). In a pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and transfected HEK293a cells Hhat localized to the endoplasmic reticulum. siRNA knockdown showed that Hhat is required for Sonic hedgehog (Shh) palmitoylation, for its assembly into high molecular weight extracellular complexes and for functional activity. Hhat knockdown inhibited Hh autocrine and juxtacrine signaling, and inhibited PDAC cell growth and invasiveness in vitro. In addition, Hhat knockdown in a HEK293a cell line constitutively expressing Shh and A549 human non-small cell lung cancer cells inhibited their ability to signal in a juxtacrine/paracrine fashion to the reporter cell lines C3H10T1/2 and Shh-Light2. Our data identify Hhat as a key player in Hh-dependent signaling and tumour cell transformed behaviour.",

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AB - Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers. To be highly active, Hedgehog proteins must be palmitoylated at their N-terminus by the MBOAT family multispanning membrane enzyme Hedgehog acyltransferase (Hhat). In a pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and transfected HEK293a cells Hhat localized to the endoplasmic reticulum. siRNA knockdown showed that Hhat is required for Sonic hedgehog (Shh) palmitoylation, for its assembly into high molecular weight extracellular complexes and for functional activity. Hhat knockdown inhibited Hh autocrine and juxtacrine signaling, and inhibited PDAC cell growth and invasiveness in vitro. In addition, Hhat knockdown in a HEK293a cell line constitutively expressing Shh and A549 human non-small cell lung cancer cells inhibited their ability to signal in a juxtacrine/paracrine fashion to the reporter cell lines C3H10T1/2 and Shh-Light2. Our data identify Hhat as a key player in Hh-dependent signaling and tumour cell transformed behaviour.

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Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells

Abstract

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