Deconstructing the Role of MALAT1 in MAPK-Signaling in Melanoma | Oncotarget
Channel: Oncotarget
Date: 2023-05-30

Oncotarget published this research paper on May 26, 2023 in Volume 14, entitled, “Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment" by researchers from the Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, San Francisco, CA; Department of Dermatology, Clinic Landstrasse Vienna, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria; School of Medicine, University of California San Francisco, San Francisco, CA.
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DOI - https://doi.org/10.18632/oncotarget.28447

Correspondence to - Valentin Feichtenschlager - valentin.feichtenschlager@ucsf.edu

Abstract

The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK and ERK in melanoma is largely unknown. We demonstrate the impacts of antisense oligonucleotide (ASO)-based MALAT1-inhibition on MAPK-pathway gene regulation in melanoma. Our results showed that MALAT1-ASO treatment decreased BRAF RNA expression and protein levels, and MALAT1 had increased correlation with MAPK-pathway associated genes in melanoma patient samples compared to healthy skin. Additionally, drug-induced MAPK inhibition upregulated MALAT1-expression, a finding that resonates with a paradigm of MALAT1-expression presented in this work: MALAT1 is downregulated in melanoma and other cancer types in which MALAT1 seems to be associated with MAPK-signaling, while MALAT1-ASO treatment strongly reduced the growth of melanoma cell lines, even in cases of resistance to MEK inhibition. MALAT1-ASO treatment significantly inhibited colony formation in vitro and reduced tumor growth in an NRAS-mutant melanoma xenograft mouse model in vivo, while showing no aberrant toxic side effects. Our findings demonstrate new insights into MALAT1-mediated MAPK-pathway gene regulation and a paradigm of MALAT1 expression in MAPK-signaling-dependent cancer types. MALAT1 maintains essential oncogenic functions, despite being downregulated.

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Keywords - MALAT1, MAPK-pathway, BRAF, melanoma, antisense oligonucleotides

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