Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment
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Valentin Feichtenschlager1,2, Yixuan James Zheng1,3, Wilson Ho1, Linan Chen1, Ciara Callanan1, Christopher Chen1, Albert Lee1, Jose Ortiz1, Klemens Rappersberger2 and Susana Ortiz-Urda1
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
|Valentin Feichtenschlager,||email:||[email protected]|
Keywords: MALAT1; MAPK-pathway; BRAF; melanoma; antisense oligonucleotides
Received: February 09, 2023 Accepted: May 15, 2023 Published: May 26, 2023
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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