The study by Unfried and colleagues reports the intriguing discovery of a novel long noncoding RNA (lncRNA) with a critical role in the regulation of DNA damage response in hepatocellular carcinoma. Providing an exhaustive and detailed characterization of the complex network interactions within the double-stranded breaks in the DNA, the authors demonstrated that NIHCOLE serves as a scaffold and facilitator of nonhomologous end-joining machinery. This study greatly contributes to the growing evidence supporting the key roles of ncRNAs in health and disease. Although larger studies are needed to understand the potential of lncRNAs to improve the clinical management of patients with cancer, this study demonstrates that high expression of NIHCOLE may be associated with an impaired response to DNA damage–based therapies, in part through its role in preventing cell death.

See related article by Unfried et al., p. 4910

Cancer therapy represents one of the greatest challenges in medicine today. Different strategies have been developed over decades to treat cancer, but we are still very far from being able to effectively cure all patients. One of the main issues is the almost inevitable emergence of resistance against currently available therapies. Furthermore, the complexity of cancer cells and cancer biology places us in a paradoxical state in which “the more we discover, the less we seem to know.” Genome-wide studies increasingly demonstrate the multiple levels at which genomes are controlled and reprogrammed in tumorigenesis. Therefore, dissecting all the factors that can control the nefarious behavior of tumor cells, including mechanisms to adapt to and resist different treatments, is extremely critical to identify novel potential therapeutic strategies that could overcome the inefficiency of available therapies.

Cancer medicine was originally based on the analysis of medical and clinical records and epidemiologic surveys, and from the very beginning, cancer development has been linked to hazard factors. Back in 1980s, carcinogenesis was described to arise from a combination of DNA mutations generated by environmental mutagen insults and the cooccurrence of DNA damage without effective repair (1, 2), pointing to the essential role of the DNA damage response (DDR) machinery in this process. Eukaryotic cells count on several systems to sense and repair DNA damage, which can in turn induce cell-cycle arrest, apoptosis, or successful DNA repair to avoid the accumulation of mutated cells (3, 4). Unfortunately, these physiologic processes are altered in cancer cells, which develop aberrant responses to DNA damage to sustain cellular proliferation despite cumulative DNA mutations, allowing the malignant cells to survive, propagate, and evolve (4, 5). Treatment of various cancers through the induction of DNA damage by chemotherapeutic agents and radiotherapy has been relatively effective over the past few decades despite the emergence of resistance in many cases. Although the mechanism of action of such therapies is not fully understood, it is accepted that DNA damaging therapies are closely based on overwhelming the DDR in cancer cells, which can lead to tumoral cell death (4, 5). However, the basic biological mechanisms underlying the DDR in cancer cells remain elusive and require further study to better understand how cancer cells can become resistant to chemo- and radiotherapies.

In this issue of Cancer Research, Unfried and colleagues identified a novel long noncoding RNA (lncRNA), NIHCOLE, which is induced in hepatocellular carcinoma (HCC) and confers a prooncogenic advantage to the cancer cells by enhancing the DDR (6). Specifically, the authors found that NIHCOLE can facilitate the elongation efficiency of double-stranded breaks (DSB), thus conferring the capacity to sustain malignant proliferation in HCC cells despite DNA-damage accumulation from replicative stress. This novel finding is in line with a growing body of evidence supporting that lncRNAs participate in the regulation of the DDR (7). However, to date, only a few studies have exhaustively described the precise involvement of lncRNAs in the repair of DSBs. The fascinating RNA biology has intrigued scientists for decades, as RNA molecules show an astonishingly wide array of biological functions, including the capacity to store genetic information, catalyze diverse biochemical reactions, protect chromatin structure, facilitate DNA translocations, and assist with DNA replication, cell division, and protein synthesis, among others (8). During the past two decades, a better understanding of ncRNA molecules has revealed that they participate in the maintenance of genome stability and can potentially influence evolution by acting as templates for genome modification (8). Furthermore, ncRNAs can inhibit spurious recombination between repetitive DNA elements, repress mobilization of transposable elements, serving as template or bridges for DSBs during repair, and direct developmentally regulated genome rearrangements (7).

In the study by Unfried and colleagues, they take a step forward towards addressing the role of a novel lncRNA in DDR regulation in HCC (6). The authors described NIHCOLE as an essential player in the ligation efficacy of blunt-ended DSBs in HCC cells, working as a scaffold component of the nonhomologous end-joining (NHEJ) machinery. At the molecular level, NIHCOLE transiently stabilized the interactions formed at DNA ends promoting short-range synapsis and enhancing ligation efficiency. The authors also demonstrated that putative structural domains of NICHOLE supported stable multimeric complexes formed by several NHEJ factors, including Ku70/80, APLF, XRCCa, and DNA ligase IV, cooperating with the scaffolding and stabilization required for DNA-end ligation by the X4L4 complex.

The authors found that NIHCOLE overexpression correlated with more aggressiveness and worse prognosis in patients with HCC, demonstrating the potential translational relevance of their findings and suggesting a key role for DDR misregulation in the clinical and pathologic development of HCC. In line with this, the authors also described a very relevant phenomenon when they depleted the lncRNA in HCC cells: NIHCOLE-depleted cells accumulated significantly higher DNA damage levels upon ionizing radiation (IR) due to decreased NHEJ repair efficiency. This phenomenon caused an increase in cell death and sensitivity to IR exposure, implying that the aberrant overexpression of NIHCOLE in liver-tumor cells might provide resistance to therapies based on DNA damaging agents. This discovery indicates that targeting NIHCOLE lncRNA could potentially be exploited therapeutically as an adjuvant to chemo- and radiotherapies, especially in those cases in which the tumors show resistance to those treatments.

Interestingly, whereas depletion of NIHCOLE in HCC cells expressing high levels of this lncRNA caused an impairment in NHEJ activity, overexpression of NIHCOLE in cells that did not basally express the lncRNA had little effect on NHEJ activity. This finding suggests that NIHCOLE overexpression may not be responsible for the reprogramming of NHEJ in cancer cells by itself but may be required for this cellular adaptation. From the translational point of view, these results indicate that targeting NIHCOLE may not be a general therapy for HCC but may represent a useful strategy for those patients presenting greater expression levels of the lncRNA. Correlation studies of NIHCOLE expression and emergence of resistance to DNA damaging therapies would help further establish the clinical implications of the research carried out by Unfried and colleagues. Additional studies will be also needed to address the potential role of this lncRNA in other types of tumors. In fact, NIHCOLE is overexpressed in colorectal, gastric, head and neck, lung, and breast cancers, suggesting that these findings could be extrapolated to additional tumors.

In summary, Unfried and colleagues have identified a novel lncRNA overexpressed in HCC cells and involved in the DDR. This work has opened important unanswered questions regarding differential sensitivity against DNA damage–based cancer therapies. The proposed mechanism of action of NIHCOLE from this study indicates that it supports multimeric complexes with NHEJ factors, promoting the ligation efficiency of DSBs and conferring aberrant proliferative advantages to the HCC cells expressing the lncRNA, and potentially granting resistance to DNA damaging therapies. In contrast, cells lacking NIHCOLE expression would have less efficient repair machineries, making them more sensitive to radiation or DNA damaging agents. This discovery suggests that stratification of patients based on the expression of lncRNAs involved in DDR in their tumors may be useful to select the most effective therapies and may pave the way for personalized therapies in HCC.

A. Lujambio reports grants from Pfizer and Genentech; personal fees from AstraZeneca; and personal fees from Exelixis outside the submitted work. No disclosures were reported by the other author.

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