Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment

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// Valentin Feichtenschlager 1 , 2 , Yixuan James Zheng 1 , 3 , Wilson Ho 1 , Linan Chen 1 , Ciara Callanan 1 , Christopher Chen 1 , Albert Lee 1 , Jose Ortiz 1 , Klemens Rappersberger 2 and Susana Ortiz-Urda 1 1 Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, San Francisco, CA 94110, USA 2 Department of Dermatology, Clinic Landstrasse Vienna, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria 3 School of Medicine, University of California San Francisco, San Francisco, CA 94110, USA Correspondence to: Valentin Feichtenschlager, email: valentin.feichtenschlager@ucsf.edu Keywords: MALAT1; MAPK-pathway; BRAF; melanoma; antisense oligonucleotides Received: February 09, 2023 Accepted: May 15, 2023 Published: May 26, 2023 Copyright: © 2023 Feichtenschlager et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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