BRN2 is a non-canonical melanoma tumor-suppressor

Michael Hamm; Pierre Sohier; Valérie Petit; Jérémy H. Raymond; Véronique Delmas; Madeleine Le Coz; Franck Gesbert; Colin Kenny; Zackie Aktary; Marie Pouteaux; Florian Rambow; Alain Sarasin; Nisamanee Charoenchon; Alfonso Bellacosa; Luis Sanchez-del-Campo; Laura Mosteo; Martin Lauss; Dies Meijer; Eirikur Steingrimsson; Göran B. Jönsson; Robert A. Cornell; Irwin Davidson; Colin R. Goding; Lionel Larue

doi:10.1038/s41467-021-23973-5

BRN2 is a non-canonical melanoma tumor-suppressor

Michael Hamm, Pierre Sohier, Valérie Petit, Jérémy H. Raymond, Véronique Delmas, Madeleine Le Coz, Franck Gesbert, Colin Kenny, Zackie Aktary, Marie Pouteaux, Florian Rambow, Alain Sarasin, Nisamanee Charoenchon, Alfonso Bellacosa, Luis Sanchez-del-Campo, Laura Mosteo, Martin Lauss, Dies Meijer, Eirikur Steingrimsson, Göran B. JönssonRobert A. Cornell, Irwin Davidson, Colin R. Goding, Lionel Larue

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8 Scopus citations

Abstract

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a Braf^V600EPten^F/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

Original language	English
Article number	3707
Pages (from-to)	3707
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23973-5
State	Published - May 17 2021

Keywords

Animals
Carcinogenesis/genetics
Cell Line, Tumor
Cell Proliferation/genetics
Chromatin Immunoprecipitation
Cohort Studies
DNA Copy Number Variations
Disease Progression
Gene Expression Regulation, Neoplastic/genetics
Gene Knockdown Techniques
Genes, Tumor Suppressor
Haploinsufficiency
Homeodomain Proteins/genetics
Humans
Immunohistochemistry
Melanoma, Cutaneous Malignant
Melanoma/genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microarray Analysis
Microphthalmia-Associated Transcription Factor/metabolism
Mutation
POU Domain Factors/genetics
PTEN Phosphohydrolase/genetics
Phosphatidylinositol 3-Kinases/metabolism
Proto-Oncogene Proteins B-raf/genetics
RNA, Small Interfering
Skin Neoplasms/genetics

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10.1038/s41467-021-23973-5

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Hamm, M., Sohier, P., Petit, V., Raymond, J. H., Delmas, V., Le Coz, M., Gesbert, F., Kenny, C., Aktary, Z., Pouteaux, M., Rambow, F., Sarasin, A., Charoenchon, N., Bellacosa, A., Sanchez-del-Campo, L., Mosteo, L., Lauss, M., Meijer, D., Steingrimsson, E., ... Larue, L. (2021). BRN2 is a non-canonical melanoma tumor-suppressor. Nature Communications, 12(1), 3707. Article 3707. https://doi.org/10.1038/s41467-021-23973-5

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title = "BRN2 is a non-canonical melanoma tumor-suppressor",

abstract = "While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.",

keywords = "Animals, Carcinogenesis/genetics, Cell Line, Tumor, Cell Proliferation/genetics, Chromatin Immunoprecipitation, Cohort Studies, DNA Copy Number Variations, Disease Progression, Gene Expression Regulation, Neoplastic/genetics, Gene Knockdown Techniques, Genes, Tumor Suppressor, Haploinsufficiency, Homeodomain Proteins/genetics, Humans, Immunohistochemistry, Melanoma, Cutaneous Malignant, Melanoma/genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microarray Analysis, Microphthalmia-Associated Transcription Factor/metabolism, Mutation, POU Domain Factors/genetics, PTEN Phosphohydrolase/genetics, Phosphatidylinositol 3-Kinases/metabolism, Proto-Oncogene Proteins B-raf/genetics, RNA, Small Interfering, Skin Neoplasms/genetics",

author = "Michael Hamm and Pierre Sohier and Val{\'e}rie Petit and Raymond, {J{\'e}r{\'e}my H.} and V{\'e}ronique Delmas and {Le Coz}, Madeleine and Franck Gesbert and Colin Kenny and Zackie Aktary and Marie Pouteaux and Florian Rambow and Alain Sarasin and Nisamanee Charoenchon and Alfonso Bellacosa and Luis Sanchez-del-Campo and Laura Mosteo and Martin Lauss and Dies Meijer and Eirikur Steingrimsson and J{\"o}nsson, {G{\"o}ran B.} and Cornell, {Robert A.} and Irwin Davidson and Goding, {Colin R.} and Lionel Larue",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = may,

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doi = "10.1038/s41467-021-23973-5",

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Hamm, M, Sohier, P, Petit, V, Raymond, JH, Delmas, V, Le Coz, M, Gesbert, F, Kenny, C, Aktary, Z, Pouteaux, M, Rambow, F, Sarasin, A, Charoenchon, N, Bellacosa, A, Sanchez-del-Campo, L, Mosteo, L, Lauss, M, Meijer, D, Steingrimsson, E, Jönsson, GB, Cornell, RA, Davidson, I, Goding, CR & Larue, L 2021, 'BRN2 is a non-canonical melanoma tumor-suppressor', Nature Communications, vol. 12, no. 1, 3707, pp. 3707. https://doi.org/10.1038/s41467-021-23973-5

TY - JOUR

T1 - BRN2 is a non-canonical melanoma tumor-suppressor

AU - Hamm, Michael

AU - Sohier, Pierre

AU - Petit, Valérie

AU - Raymond, Jérémy H.

AU - Delmas, Véronique

AU - Le Coz, Madeleine

AU - Gesbert, Franck

AU - Kenny, Colin

AU - Aktary, Zackie

AU - Pouteaux, Marie

AU - Rambow, Florian

AU - Sarasin, Alain

AU - Charoenchon, Nisamanee

AU - Bellacosa, Alfonso

AU - Sanchez-del-Campo, Luis

AU - Mosteo, Laura

AU - Lauss, Martin

AU - Meijer, Dies

AU - Steingrimsson, Eirikur

AU - Jönsson, Göran B.

AU - Cornell, Robert A.

AU - Davidson, Irwin

AU - Goding, Colin R.

AU - Larue, Lionel

PY - 2021/5/17

Y1 - 2021/5/17

N2 - While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

AB - While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

KW - Animals

KW - Carcinogenesis/genetics

KW - Cell Line, Tumor

KW - Cell Proliferation/genetics

KW - Chromatin Immunoprecipitation

KW - Cohort Studies

KW - DNA Copy Number Variations

KW - Disease Progression

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Gene Knockdown Techniques

KW - Genes, Tumor Suppressor

KW - Haploinsufficiency

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Immunohistochemistry

KW - Melanoma, Cutaneous Malignant

KW - Melanoma/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Microarray Analysis

KW - Microphthalmia-Associated Transcription Factor/metabolism

KW - Mutation

KW - POU Domain Factors/genetics

KW - PTEN Phosphohydrolase/genetics

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Proto-Oncogene Proteins B-raf/genetics

KW - RNA, Small Interfering

KW - Skin Neoplasms/genetics

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U2 - 10.1038/s41467-021-23973-5

DO - 10.1038/s41467-021-23973-5

M3 - Article

C2 - 34140478

SN - 2041-1723

VL - 12

SP - 3707

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3707

ER -

BRN2 is a non-canonical melanoma tumor-suppressor

Abstract

Keywords

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