Long non-coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation

Area of Science:

• Oncology
• Molecular Biology
• RNA Biology

Background:

• Melanoma metastasis is driven by a transition to invasive phenotypes, which also confers therapy resistance.
• Understanding the mechanisms maintaining the invasive phenotype is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of the long non-coding RNA TINCR in melanoma invasion and metastasis.
• To elucidate the molecular mechanisms by which TINCR regulates the invasive phenotype.

Main Methods:

• Analysis of TINCR expression in metastatic melanoma.
• In vitro and in vivo assays to assess the impact of TINCR depletion/re-expression on melanoma cell behavior and tumor growth.
• Investigation of TINCR's interaction with mRNAs and its effect on protein translation, focusing on ATF4 and the integrated stress response (ISR).

Main Results:

• TINCR is downregulated in metastatic melanoma.
• TINCR depletion enhances invasive markers, migration, tumor growth, and resistance to BRAF/MEK inhibitors.
• TINCR depletion activates ATF4 and ISR pathways, increasing global protein synthesis and translation of specific mRNAs.
• TINCR re-expression suppresses invasion, reduces tumor-initiating cells and metastasis, and increases drug sensitivity.
• TINCR directly binds to invasive phenotype-associated mRNAs, including ATF4, inhibiting their ribosomal binding.

Conclusions:

• TINCR acts as a suppressor of the melanoma invasive phenotype.
• TINCR functions by repressing the translation of specific ISR RNAs, including ATF4, even in nutrient-rich conditions.
• Restoring TINCR holds therapeutic potential for inhibiting melanoma metastasis and overcoming drug resistance.