Uncovering a novel pathway for p16 silencing: Therapeutic implications for lung cancer

Abstract

A key step during onset of most cases of non-small cell lung cancer (NSCLC) is the loss of the tumor suppressor p16 INK4a (best known as p16), commonly due to promoter hypermethylation. We recently reported a novel regulatory pathway involving E6-associated protein and cell division control protein 6, which provides a methylation-independent mechanism for p16 silencing in patients with a particularly aggressive form of NSCLC. CommentaryNon-small cell lung cancer (NSCLC), constituting 80% of all lung cancers, is the leading cause of cancer-related mortality worldwide. Despite important advances in treatment, the disease is rarely curable and prognosis is poor, with a dismal overall 5-year survival rate of only 20%. This highlights the importance of enhancing our knowledge of the underlying molecular events of NSCLC to develop rationally designed methods for early detection and prevention, as well as to discover novel therapeutics approaches for treatment of this disease.The most common genetic event leading to NSCLC is loss of the tumor suppressor p16 INK4a (best known as p16), occurring in »70% of patients. P16, together with the key tumor suppressors p14 ARF and p15 INK4b , is encoded in the INK4/ARF locus, one of the genomic regions most commonly affected in human cancers. Consistent with the role of p16 as a tumor suppressor, low p16 levels are associated with poor prognosis and therapeutic resistance of NSCLC patients. Understanding the mechanisms leading to p16 loss in NSCLC is central to restoring its tumor suppression and improve patient prognosis. Several mechanisms have been defined to explain the loss of p16 in NSCLC: epigenetic silencing of the entire INK4/ARF locus, genetic deletions and mutation of the gene encoding p16 (CDKN2A), and CDKN2A promoter hypermethylation; this last mode being the most common (»37% of the patients) (Fig. 1). Together, these account for the loss of p16 in two-thirds of NSCLC cases, but the molecular explanation for the remaining cases is unknown. In our recent study published in Science Signaling we addressed, at least in part, this gap in knowledge. 1 We unraveled a novel mechanism for the reduction of p16, involving the E3 ubiquitin ligase and transcriptional cofactor, E6-associated protein (E6AP), which we found to be lowly expressed in certain NSCLCs.Our analysis identified E6AP as a positive regulator of the INK4/ARF locus. Mechanistically, we showed that E6AP controls this locus by reducing the ability of E2F transcription factor 1 (E2F1) to bind to the cell division control protein 6 (CDC6) promoter. CDC6 is a repressor of the INK4/ARF locus, and consequently low E6AP levels relieve this repression by CDC6 (Fig. 1). The extent by which E2F1 activity was inhibited by E6AP was comparable to that achieved by retinoblastoma protein (RB1, best known as pRb), the key inhibitor of E2F1 during the cell cycle. However, this action of E6AP is independent of pRb.We demonstrated the clinical relevance of the E6AP-CDC6-p16 axis by analyzing NSCLC human samples. This an...

The Expression of Histone Acetyltransferase KAT6A in Non-small Cell Lung Cancer

“…The role of KAT6A in NSCLC was also indicated by Gamell et al (38). The authors (38) described the way KAT6A might affect p16 expression (tumor suppressor protein whose expression is lost in NSCLC cases) (38).…”

“…The role of KAT6A in NSCLC was also indicated by Gamell et al (38). The authors (38) described the way KAT6A might affect p16 expression (tumor suppressor protein whose expression is lost in NSCLC cases) (38). The loss of p16 expression in NSCLC occurs commonly through promoter hypermethylation, but other modes that contribute to p16 absence can also be distinguished (38,39).…”

“…The authors (38) described the way KAT6A might affect p16 expression (tumor suppressor protein whose expression is lost in NSCLC cases) (38). The loss of p16 expression in NSCLC occurs commonly through promoter hypermethylation, but other modes that contribute to p16 absence can also be distinguished (38,39). Gamell et al (38,39) showed the methylation-independent manner leading to the loss of p16 expression in NSCLC (38,39).…”

E6AP Promotes a Metastatic Phenotype in Prostate Cancer

“…This effect of E6AP has been largely linked to the degradation of p53, thereby overcoming viral-induced growth inhibition (Beaudenon and Huibregtse, 2008). Over the past decade, E6AP has been also linked to viral-independent cancers, including B-cell lymphoma and lung cancer (Gamell et al., 2017b, Wolyniec et al., 2012). Pertinent to this study, E6AP has been strongly linked to prostate development and PC.…”

Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis

“…Overregulated and downregulated DEGs in CCP analysis of lung cancer and other types of cancer. References [ 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 ,…”