Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis

Lisa Ta; Brandon L Tsai; Weixian Deng; Jihui Sha; Grigor Varuzhanyan; Wendy Tran; James A Wohlschlegel; Janai R Carr-Ascher; Owen N Witte

doi:10.1016/j.isci.2023.108480

Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis

iScience. 2023 Nov 17;26(12):108480. doi: 10.1016/j.isci.2023.108480. eCollection 2023 Dec 15.

Authors

Lisa Ta¹, Brandon L Tsai², Weixian Deng³, Jihui Sha³, Grigor Varuzhanyan⁴, Wendy Tran⁴, James A Wohlschlegel³, Janai R Carr-Ascher^{5

6}, Owen N Witte^{1

4

7

8

9

10}

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles; Los Angeles, CA 90095, USA.
² Department of Human Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA.
³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA.
⁵ Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis, Sacramento, CA 95817, USA.
⁶ Department of Orthopedic Surgery, University of California, Davis; Sacramento, CA 95817, USA.
⁷ Molecular Biology Institute, University of California, Los Angeles; Los Angeles, CA 90095, USA.
⁸ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Los Angeles, CA 90095, USA.
¹⁰ Parker Institute for Cancer Immunotherapy, University of California, Los Angeles; Los Angeles, CA 90095, USA.

Abstract

Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway. A role for non-mutated Raf in metastasis is also emerging, but the key mechanisms remain unclear. Elevated expression of any of the three wild-type Raf family members (C, A, or B) can drive metastasis. We utilized an in vivo model to show that wild-type C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage-dependent manner. Analysis of the transcriptomic and phosphoproteomic landscape indicated that C-Raf-driven metastasis is accompanied by upregulated MAPK signaling. Use of C-Raf mutants demonstrated that the dimerization domain, but not its kinase activity, is essential for metastasis. Endogenous Raf monomer knockouts revealed that C-Raf's ability to form dimers with endogenous Raf molecules is important for promoting metastasis. These data identify wild-type C-Raf heterodimer signaling as a potential target for treating metastatic disease.

Keywords: Biochemistry; Cancer; Molecular biology; Proteomics; Transcriptomics.

Abstract

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