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

Abstract

Transition from proliferative‐to‐invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down‐regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR‐depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re‐expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor‐initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient‐rich conditions by repressing translation of selected ISR RNAs.

Genetic predisposition to papillary thyroid carcinoma is mediated by a long non-coding RNA TINCR enhancer polymorphism

“…The high expression of TINCR and its carcinogenic effect were also observed in epithelial ovarian cancer 28 , breast cancer 18 , cervical squamous cell carcinoma 29 , hepatocellular carcinoma 30 , non-small cell lung cancer 31 , nasopharyngeal carcinoma 32 , and bladder urothelial carcinoma 33 , which suggests that TINCR may be a strategic target for cancer treatment. However, the opposite situation was found in lung adenocarcinoma 34 , colorectal cancer 35 , prostate cancer 36 , melanoma 37 , oral squamous cell carcinoma 38 , and skin cancer 39 , with a down-regulation in these cancers.…”

Regulation of LncRNAs in Melanoma and Their Functional Roles in the Metastatic Process

“…Consistently, metastatic melanomas display very low levels of TINCR RNA. Restoration of high-level expression of TINCR in metastatic melanomas reverts the invasive phenotype, thus demonstrating the direct involvement of TINCR in the metastatic process [44]. Importantly, TINCR was described as an oncogene in other cancers, acting as ceRNA for various miRNAs.…”

“…We identified TINCR lncRNA as a suppressor of melanoma invasion and metastasis formation [44]. TINCR expression prevents translational reprogramming, activation of ATF4, and stress response in melanoma.…”

“…Nuclear lncRNAs perform these functions by different mechanisms, by acting, for example, as scaffolds that regulate chromatin architecture or recruit chromatin-modifying enzymes (XIST, HOTAIR, DLX6AS [28][29][30][31], regulating long-range chromatin interactions [32][33][34], or regulating transcription directly by forming R-loops or interfering with the Pol II machinery [35][36][37]. Cytoplasmic lncRNAs are frequently involved in regulating mRNA turnover by different mechanisms [38][39][40][41], including association with ribosomes and direct translation-regulation [42][43][44]. An increasing body of evidence suggests that lncRNAs can also be translated, giving rise to micropeptides encoded by small ORFs [45][46][47][48].…”

“…A growing body of evidence suggests that lncRNAs are aberrantly expressed and deregulated in cancer, functioning as tumor suppressors or oncogenes [19,53]. Given the multiple mechanisms of action known for lncRNAs, it is not surprising that the same lncR-NAs may exert dual functions in cancer, acting as either tumor suppressors or oncogenes, depending on the cancer type (H19, BANCR, TINCR, MALAT, XIST) [44,[54][55][56][57][58][59].…”