The basal transcription machinery as a target for cancer therapy

Abstract

General transcription is required for the growth and survival of all living cells. However, tumor cells require extraordinary levels of transcription, including the transcription of ribosomal RNA genes by RNA polymerase I (RNPI) and mRNA by RNA polymerase II (RNPII). In fact, cancer cells have mutations that directly enhance transcription and are frequently required for cancer transformation. For example, the recent discovery that MYC enhances the transcription of the majority genes in the genome correlates with the fact that several transcription interfering drugs preferentially kill cancer cells. In recent years, advances in the mechanistic studies of the basal transcription machinery and the discovery of drugs that interfere with multiple components of transcription are being used to combat cancer. For example, drugs such as triptolide that targets the general transcription factors TFIIH and JQ1 to inhibit BRD4 are administered to target the high proliferative rate of cancer cells. Given the importance of finding new strategies to preferentially sensitize tumor cells, this review primarily focuses on several transcription inhibitory drugs to demonstrate that the basal transcription machinery constitutes a potential target for the design of novel cancer drugs. We highlight the drugs' mechanisms for interfering with tumor cell survival, their importance in cancer treatment and the challenges of clinical application.

Figure 1

Different subunits of protein complexes involved in basal in basal transcription have different enzymatic activities that are or can be target by drugs inhibiting RNPII transcription. In the case of BRD4, in addition to its kinase activity, the Brm domain is the target of JQ1 and I-BET151, which interferes with the binding to acetylated histones; therefore future drugs that target components of the basal transcription machinery could be designed to interfere the interaction between different subunits into the complex. The different subunits with enzymatic activities of a corresponding complex are indicated in the figure.

Figure 2

Cancer cells require high levels of basal transcription. To maintain a proliferative state cancer cells need active transcription by the three RNA polymerases. In particular the expression of oncogenes as well genes that suppress apoptosis is enhanced in tumour cells. Also, the enhancement of global transcription by MYC is necessary to maintain the cancerous phenotype. This situation is similar to the requirements of the transcription activity in ectopic expression genes, which is more sensible to the reduction of global transcription than normally expressed genes. Different kind of genes in the genome, require different levels of transcriptional activity. For instance, metabolic and regulatory genes do not require high levels of transcriptional activity. On the other hand, genes that express product of terminal differentiation require higher levels of transcriptional activity. Unregulated and ectopically expressed genes as well as overexpressed genes as response to stress, a situation that occurs in many cancers, require even higher transcriptional activity to maintain a transformed phenotype. Therefore, the reduction of the basal transcription activity preferentially affects these genes.

Figure 3

Transcription inhibitors affect differentially regulatory sequences of genes and trigger cell death in cancer cells. A) Transcription inhibitors differentially affect the regulatory sequences of genes and trigger cell death in cancer cells. This fact is related to requirement of transcription factors or coactivators recruited on regulatory sequences such as enhancers and promoters. Typical enhancers recruit several transcription factors and coactivators in order to enhance transcription of downstream gene; however, super-enhancer needs an excess of transcription than a typical enhancer, rendering the gene very sensitive to transcription perturbation. Similarly, transgene overexpression (whose promoter contain specific sequences for transactivators or specific cis elements), has been demonstrated to be affected by transcription inhibitors o genetic deficient in transcription [94,95]. In all cases, the final result is the depletion of messenger RNAs mainly genes that showed a high level of expression such as oncogenes. B) Cancer cells are more sensitive to suffer cell death after exposition to transcription inhibitors compared with normal cells. As we have seen before, transcription inhibitors cause a depletion of messenger RNAs mainly oncogenes and overexpressed genes; however, because cancer cells are oncogene-dependent for survival, their depletion triggers cell death preferentially in cancer cells, while preserving normal cells. This principle represents a strategic point for designing drug that targets directly cancer cells.