Englander Institute for Precision Medicine

Cooperativity of c-MYC with Krüppel-Like Factor 6 Splice Variant 1 induces phenotypic plasticity and promotes prostate cancer progression and metastasis.

TitleCooperativity of c-MYC with Krüppel-Like Factor 6 Splice Variant 1 induces phenotypic plasticity and promotes prostate cancer progression and metastasis.
Publication TypeJournal Article
Year of Publication2024
AuthorsIzadmehr S, Fernandez-Hernandez H, Wiredja D, Kirschenbaum A, Lee-Poturalski C, Tavassoli P, Yao S, Schlatzer D, Hoon D, Difeo A, Levine AC, Mosquera J-M, Galsky MD, Cordon-Cardo C, Narla G
JournalbioRxiv
Date Published2024 Feb 01
Abstract

Metastasis remains a major cause of morbidity and mortality in men with prostate cancer, and the functional impact of the genetic alterations, alone or in combination, driving metastatic disease remains incompletely understood. The proto-oncogene c-MYC, commonly deregulated in prostate cancer. Transgenic expression of c-MYC is sufficient to drive the progression to prostatic intraepithelial neoplasia and ultimately to moderately differentiated localized primary tumors, however, c-MYC-driven tumors are unable to progress through the metastatic cascade, suggesting that a "second-hit" is necessary in the milieu of aberrant c-MYC-driven signaling. Here, we identified cooperativity between c-MYC and KLF6-SV1, an oncogenic splice variant of the KLF6 gene. Transgenic mice that co-expressed KLF6-SV1 and c-MYC developed progressive and metastatic prostate cancer with a histological and molecular phenotype like human prostate cancer. Silencing c-MYC expression significantly reduced tumor burden in these mice supporting the necessity for c-MYC in tumor maintenance. Unbiased global proteomic analysis of tumors from these mice revealed significantly enriched vimentin, a dedifferentiation and pro-metastatic marker, induced by KLF6-SV1. c-MYC-positive tumors were also significantly enriched for KLF6-SV1 in human prostate cancer specimens. Our findings provide evidence that KLF6-SV1 is an enhancer of c-MYC-driven prostate cancer progression and metastasis, and a correlated genetic event in human prostate cancer with potential translational significance.

DOI10.1101/2024.01.30.577982
Alternate JournalbioRxiv
PubMed ID38352401
PubMed Central IDPMC10862900
Grant ListKL2 RR029885 / RR / NCRR NIH HHS / United States
R01 CA181654 / CA / NCI NIH HHS / United States
U54 OD020353 / OD / NIH HHS / United States

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