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

Maciej Ciesla; Phuong Cao Thi Ngoc; Maria Eugenia Cordero Concha; Álvaro Sejas Martínez; 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 Campos; 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 Ciesla, Phuong Cao Thi Ngoc, Maria Eugenia Cordero Concha, Álvaro Sejas Martínez, 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 Campos, Cristian Bellodi

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

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
Number of pages	28
Journal	Molecular Cell
Volume	81
Issue number	7
DOIs	https://doi.org/10.1016/j.molcel.2021.01.034
Publication status	Published - 2021 Apr 1

Subject classification (UKÄ)

Cell and Molecular Biology
Biochemistry and Molecular Biology
Cancer and Oncology

Free keywords

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

UN SDGs

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

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10.1016/j.molcel.2021.01.034Licence: CC BY

1 Doctoral Thesis (compilation)

RNA modifications and post-transcriptional control in cancer and stem cells
Beneventi, G., 2021, Lund: Lund University, Faculty of Medicine. 82 p.
Research output: Thesis › Doctoral Thesis (compilation)

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Ciesla, M., Cao Thi Ngoc, P., Cordero Concha, M. E., Sejas Martínez, Á., 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). 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 = "DRP1, MYC, SF3A3, alternative splicing, cancer plasticity, cancer stem cells, eIF3D, mitochondrial dynamics, translation control, triple-negative breast cancer",

author = "Maciej Ciesla and {Cao Thi Ngoc}, Phuong and {Cordero Concha}, {Maria Eugenia} and {Sejas Mart{\'i}nez}, {\'A}lvaro 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 {Bosch Campos}, Ana and Cristian Bellodi",

year = "2021",

month = apr,

day = "1",

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

language = "English",

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Ciesla, M, Cao Thi Ngoc, P, Cordero Concha, ME, Sejas Martínez, Á, 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 Campos, A & Bellodi, C 2021, 'Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer', Molecular Cell, vol. 81, no. 7. 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 - Ciesla, Maciej

AU - Cao Thi Ngoc, Phuong

AU - Cordero Concha, Maria Eugenia

AU - Sejas Martínez, Álvaro

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 Campos, Ana

AU - Bellodi, Cristian

PY - 2021/4/1

Y1 - 2021/4/1

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 - DRP1

KW - MYC

KW - SF3A3

KW - alternative splicing

KW - cancer plasticity

KW - cancer stem cells

KW - eIF3D

KW - mitochondrial dynamics

KW - translation control

KW - triple-negative breast cancer

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

JO - Molecular Cell

JF - Molecular Cell

IS - 7

ER -

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

Abstract

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

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Research output

RNA modifications and post-transcriptional control in cancer and stem cells

Cite this