Adaptive Transcriptional Responses by CRTC Coactivators in Cancer

Abstract

Adaptive stress signaling networks directly influence tumor development and progression. These pathways mediate responses that allow cancer cells to cope with both tumor cell-intrinsic and cell-extrinsic insults and develop acquired resistance to therapeutic interventions. This is mediated in part by constant oncogenic rewiring at the transcriptional level by integration of extracellular cues that promote cell survival and malignant transformation. The cAMP-regulated transcriptional coactivators (CRTCs) are a newly discovered family of intracellular signaling integrators that serve as the conduit to the basic transcriptional machinery to regulate a host of adaptive response genes. Thus, somatic alterations that lead to CRTC activation are emerging as key driver events in the development and progression of many tumor subtypes.

Keywords: adaptive stress signaling; cAMP-regulated transcriptional coactivators (CRTCs); cAMP-response element-binding protein (CREB); cancer; signal transduction; transcription.

Figure 1.. Post-translational Modifications Regulate CRTC Function.

Schematic of the CRTC1–3 family protein structures with known functional domains denoted with the locations of key regulatory PTMs (left). Summary of the types of PTMs, amino acid residue position, enzyme responsible for the PTM, and the effect of each PTM on CRTC13 function (right). Abbreviations: A, acetylation (grey), CBD, CREB binding domain; CRTC, cAMP-regulated transcriptional coactivator; M, methylation (red); P, phosphorylation (blue); PTM, post-translational modification; RD, regulatory domain; SD, serine/glutamine-rich splicing domain; TAD, transactivation domain; U, ubiquitination (green).

Figure 2.. Catalog of CRTC Aberrations in Cancer.

Overview of The Cancer Genome Atlas (TCGA) PanCan data summarizing the frequencies and distribution of somatic mutations, gene fusions, amplifications, deletions, and mRNA expression in CRTC1–3 across a subset of cancers. Mutations in amino acid residues that have known regulatory roles are depicted with large blue circles in the lollipop plots in contrast to mutations with unknown roles that are depicted with small red circles. Abbreviations: CBD, CREB binding domain; CRTC, cAMP-regulated transcriptional coactivator; RD, regulatory domain; SD, serine/glutamine-rich splicing domain; TAD, transactivation domain.

Figure 3.. Hallmarks of the CRTC Adaptive Stress Regulators and Cancer.

The impact of CRTCs, on the next generation of hallmarks of cancer, are annotated to highlight specific examples of directly regulated target genes that are involved in tumorigenesis and progression. Each concentric ring moving out from the CRTC core provides information regarding the functional role as either an oncogene or tumor suppressor, the specific CRTC family member involved, and the type of cancer reported. The outer ring represents the cancer hallmarks specifically controlled by the CRTCs. Abbreviations: Ca, carcinoma; CRTC, cAMP-regulated transcriptional coactivator; ESCC, esophageal squamous cell carcinoma; MEC, mucoepidermoid carcinoma; NR, not reported; NSCLC, non-small cell lung cancer; OG, oncogene; TS, tumor suppressor.