Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer

Maciej Cieśla; Phuong Cao Thi Ngoc; Eugenia Cordero; Álvaro Sejas Martinez; Mikkel Morsing; Sowndarya Muthukumar; Giulia Beneventi; Magdalena Madej; Roberto Munita; Terese Jönsson; Kristina Lövgren; Anna Ebbesson; Björn Nodin; Ingrid Hedenfalk; Karin Jirström; Johan Vallon-Christersson; Gabriella Honeth; Johan Staaf; Danny Incarnato; Kristian Pietras; Ana Bosch; Cristian Bellodi

doi:10.1016/j.molcel.2021.01.034

Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer

Maciej Cieśla, Phuong Cao Thi Ngoc, Eugenia Cordero, Álvaro Sejas Martinez, Mikkel Morsing, Sowndarya Muthukumar, Giulia Beneventi, Magdalena Madej, Roberto Munita, Terese Jönsson, Kristina Lövgren, Anna Ebbesson, Björn Nodin, Ingrid Hedenfalk, Karin Jirström, Johan Vallon-Christersson, Gabriella Honeth, Johan Staaf, Danny Incarnato, Kristian PietrasAna Bosch^*, Cristian Bellodi^*

^*Corresponding author for this work

Molecular Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.

Original language	English
Article number	j.molcel.2021.01.034
Pages (from-to)	1453-1468
Number of pages	16
Journal	Molecular Cell
Volume	81
Issue number	7
Early online date	3-Mar-2021
DOIs	https://doi.org/10.1016/j.molcel.2021.01.034
Publication status	Published - Apr-2021

Keywords

alternative splicing
MYC
SF3A3
translation control
eIF3D
mitochondrial dynamics
DRP1
triple-negative breast cancer
cancer stem cells
cancer plasticity

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Cieśla, M., Ngoc, P. C. T., Cordero, E., Martinez, Á. S., Morsing, M., Muthukumar, S., Beneventi, G., Madej, M., Munita, R., Jönsson, T., Lövgren, K., Ebbesson, A., Nodin, B., Hedenfalk, I., Jirström, K., Vallon-Christersson, J., Honeth, G., Staaf, J., Incarnato, D., ... Bellodi, C. (2021). Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer. Molecular Cell, 81(7), 1453-1468. Article j.molcel.2021.01.034. https://doi.org/10.1016/j.molcel.2021.01.034

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title = "Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer",

abstract = "Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.",

keywords = "alternative splicing, MYC, SF3A3, translation control, eIF3D, mitochondrial dynamics, DRP1, triple-negative breast cancer, cancer stem cells, cancer plasticity",

author = "Maciej Cie{\'s}la and Ngoc, {Phuong Cao Thi} and Eugenia Cordero and Martinez, {{\'A}lvaro Sejas} and Mikkel Morsing and Sowndarya Muthukumar and Giulia Beneventi and Magdalena Madej and Roberto Munita and Terese J{\"o}nsson and Kristina L{\"o}vgren and Anna Ebbesson and Bj{\"o}rn Nodin and Ingrid Hedenfalk and Karin Jirstr{\"o}m and Johan Vallon-Christersson and Gabriella Honeth and Johan Staaf and Danny Incarnato and Kristian Pietras and Ana Bosch and Cristian Bellodi",

year = "2021",

month = apr,

doi = "10.1016/j.molcel.2021.01.034",

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Cieśla, M, Ngoc, PCT, Cordero, E, Martinez, ÁS, Morsing, M, Muthukumar, S, Beneventi, G, Madej, M, Munita, R, Jönsson, T, Lövgren, K, Ebbesson, A, Nodin, B, Hedenfalk, I, Jirström, K, Vallon-Christersson, J, Honeth, G, Staaf, J, Incarnato, D, Pietras, K, Bosch, A & Bellodi, C 2021, 'Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer', Molecular Cell, vol. 81, no. 7, j.molcel.2021.01.034, pp. 1453-1468. https://doi.org/10.1016/j.molcel.2021.01.034

TY - JOUR

T1 - Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer

AU - Cieśla, Maciej

AU - Ngoc, Phuong Cao Thi

AU - Cordero, Eugenia

AU - Martinez, Álvaro Sejas

AU - Morsing, Mikkel

AU - Muthukumar, Sowndarya

AU - Beneventi, Giulia

AU - Madej, Magdalena

AU - Munita, Roberto

AU - Jönsson, Terese

AU - Lövgren, Kristina

AU - Ebbesson, Anna

AU - Nodin, Björn

AU - Hedenfalk, Ingrid

AU - Jirström, Karin

AU - Vallon-Christersson, Johan

AU - Honeth, Gabriella

AU - Staaf, Johan

AU - Incarnato, Danny

AU - Pietras, Kristian

AU - Bosch, Ana

AU - Bellodi, Cristian

PY - 2021/4

Y1 - 2021/4

N2 - Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.

AB - Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.

KW - alternative splicing

KW - MYC

KW - SF3A3

KW - translation control

KW - eIF3D

KW - mitochondrial dynamics

KW - DRP1

KW - triple-negative breast cancer

KW - cancer stem cells

KW - cancer plasticity

U2 - 10.1016/j.molcel.2021.01.034

DO - 10.1016/j.molcel.2021.01.034

M3 - Article

C2 - 33662273

SN - 1097-2765

VL - 81

SP - 1453

EP - 1468

JO - Molecular Cell

JF - Molecular Cell

IS - 7

M1 - j.molcel.2021.01.034

ER -

Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer

Abstract

Keywords

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