miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking

Katherine A. Pillman; Caroline A. Phillips; Suraya Roslan; John Toubia; B. Kate Dredge; Andrew G. Bert; Rachael Lumb; Daniel P. Neumann; Xiaochun Li; Simon J. Conn; Dawei Liu; Cameron P. Bracken; David M. Lawrence; Nataly Stylianou; Andreas W. Schreiber; Wayne D. Tilley; Brett G Hollier; Yeesim Khew-Goodall; Luke A. Selth; Gregory J. Goodall; Philip A. Gregory

doi:10.15252/embj.201899016

miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking

Katherine A. Pillman, Caroline A. Phillips, Suraya Roslan, John Toubia, B. Kate Dredge, Andrew G. Bert, Rachael Lumb, Daniel P. Neumann, Xiaochun Li, Simon J. Conn, Dawei Liu, Cameron P. Bracken, David M. Lawrence, Nataly Stylianou, Andreas W. Schreiber, Wayne D. Tilley, Brett G Hollier, Yeesim Khew-Goodall, Luke A. Selth, Gregory J. GoodallPhilip A. Gregory

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Abstract

Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial–mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA-binding protein Quaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.

Original language	English
Article number	e99016
Number of pages	20
Journal	EMBO Journal
Volume	37
Issue number	13
DOIs	https://doi.org/10.15252/embj.201899016
Publication status	Published - 2 Jul 2018

Bibliographical note

ª 2018 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

genes
cancer cells
Quaking
epithelial–mesenchymal transition
alternative splicing
miR-375
miR-200

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Pillman_miR_P2018Final published version, 2.29 MBLicence: CC BY

Cite this

Pillman, K. A., Phillips, C. A., Roslan, S., Toubia, J., Dredge, B. K., Bert, A. G., Lumb, R., Neumann, D. P., Li, X., Conn, S. J., Liu, D., Bracken, C. P., Lawrence, D. M., Stylianou, N., Schreiber, A. W., Tilley, W. D., Hollier, B. G., Khew-Goodall, Y., Selth, L. A., ... Gregory, P. A. (2018). miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking. EMBO Journal, 37(13), Article e99016. https://doi.org/10.15252/embj.201899016

@article{3a116575d0e4402fb4037f626be5b830,

title = "miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking",

abstract = "Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial–mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA-binding protein Quaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.",

keywords = "genes, cancer cells, Quaking, epithelial–mesenchymal transition, alternative splicing, miR-375, miR-200",

author = "Pillman, {Katherine A.} and Phillips, {Caroline A.} and Suraya Roslan and John Toubia and Dredge, {B. Kate} and Bert, {Andrew G.} and Rachael Lumb and Neumann, {Daniel P.} and Xiaochun Li and Conn, {Simon J.} and Dawei Liu and Bracken, {Cameron P.} and Lawrence, {David M.} and Nataly Stylianou and Schreiber, {Andreas W.} and Tilley, {Wayne D.} and Hollier, {Brett G} and Yeesim Khew-Goodall and Selth, {Luke A.} and Goodall, {Gregory J.} and Gregory, {Philip A.}",

note = "ª 2018 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2018",

month = jul,

day = "2",

doi = "10.15252/embj.201899016",

language = "English",

volume = "37",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Wiley-VCH Verlag",

number = "13",

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Pillman, KA, Phillips, CA, Roslan, S, Toubia, J, Dredge, BK, Bert, AG, Lumb, R, Neumann, DP, Li, X, Conn, SJ, Liu, D, Bracken, CP, Lawrence, DM, Stylianou, N, Schreiber, AW, Tilley, WD, Hollier, BG, Khew-Goodall, Y, Selth, LA, Goodall, GJ & Gregory, PA 2018, 'miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking', EMBO Journal, vol. 37, no. 13, e99016. https://doi.org/10.15252/embj.201899016

TY - JOUR

T1 - miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking

AU - Pillman, Katherine A.

AU - Phillips, Caroline A.

AU - Roslan, Suraya

AU - Toubia, John

AU - Dredge, B. Kate

AU - Bert, Andrew G.

AU - Lumb, Rachael

AU - Neumann, Daniel P.

AU - Li, Xiaochun

AU - Conn, Simon J.

AU - Liu, Dawei

AU - Bracken, Cameron P.

AU - Lawrence, David M.

AU - Stylianou, Nataly

AU - Schreiber, Andreas W.

AU - Tilley, Wayne D.

AU - Hollier, Brett G

AU - Khew-Goodall, Yeesim

AU - Selth, Luke A.

AU - Goodall, Gregory J.

AU - Gregory, Philip A.

N1 - ª 2018 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2018/7/2

Y1 - 2018/7/2

N2 - Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial–mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA-binding protein Quaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.

AB - Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial–mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA-binding protein Quaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.

KW - genes

KW - cancer cells

KW - Quaking

KW - epithelial–mesenchymal transition

KW - alternative splicing

KW - miR-375

KW - miR-200

UR - http://purl.org/au-research/grants/NHMRC/1068773

UR - http://purl.org/au-research/grants/NHMRC/1128479

UR - http://purl.org/au-research/grants/NHMRC/1083961

UR - http://www.scopus.com/inward/record.url?scp=85049357305&partnerID=8YFLogxK

U2 - 10.15252/embj.201899016

DO - 10.15252/embj.201899016

M3 - Article

SN - 0261-4189

VL - 37

JO - EMBO Journal

JF - EMBO Journal

IS - 13

M1 - e99016

ER -

miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking

Abstract

Bibliographical note

Keywords

UN SDGs

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