Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

Abstract

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.

Expression profile of the amino acid transporters SLC 7A5, SLC 7A7, SLC 7A8 and the enzyme TDO 2 in basal cell carcinoma

“…PLIN4 , LEP , PLIN1 , ADIPOQ ) and inhibition of peptidases and proteinases ( SERPINA12 , TIMP4 ). Tables and present the top 25 most upregulated and downregulated genes including genes overlapping with results from other studies of BCC gene expression . GO analysis presented 211 enriched terms (Table S3; see Supporting Information) and one of the top candidate terms was the term Plasma membrane part (corrected P < 10 –8 , GO:0044459), branching into Intrinsic component of plasma membrane (GO:0031226) and Plasma membrane region (GO:0098590).…”

“…upregulated MDK , DUSP10 , TSPAN4 , SLC7A8 , TOP2A , SHOX2 and downregulated FABP4 , ADH1B , ABCC3 , LPL , COBL , TGFBR3 ) . The gene coding for osteopontin ( SPP1 ), a multifunctional protein involved in cancer development and with promising clinical utilization, was upregulated 70‐fold …”

The contributions of cancer cell metabolism to metastasis

“…Enhancer regions (Box 1) are a focus of current attention since they are highly deregulated in cancer and are the most frequently mutated non-coding regions in human tumours (Abraham et al, 2017; Bal et al, 2017; Bradner et al, 2017; Chapuy et al, 2013; Herz et al, 2014; Mansour et al, 2014; Michailidou et al, 2017; Oldridge et al, 2015; Puente et al, 2015). Interestingly, the acetylation of histone H3K27 at specific enhancers is also required to generate metastatic pancreatic ductal adenocarcinoma (PDA) cells, as seen in a PDA organoid culture system (Roe et al, 2017).…”

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

“…Increasingly evidences implicate that enhancers are functionally important in key cellular processes including cell development, differentiation and apoptosis. eRNAs are generated by the transcription of active enhancers and involve in the development of various diseases by regulating the expression of multiple genes . GREB1 is shown to be one of the most oestrogen‐specific genes and plays an important role in oestrogen‐mediated transcriptional activation.…”

“…For the group of eGREB1 knockdown with oestrogen treatment, the cell proliferation was obviously decreased ( Figure 3A, B, P < 0.01 in T24 and 5637); the cell migration ratio were reduced by 11.68% in T24 and 18.28% in 5637 ( Figure 3C-E, P < 0.001 in T24 and 5637); the invasive ability of the cells is also prominently weakened ( Figure 4A-C, P < 0.01 in T24 and 5637); ELISA assay showed that the activity of caspase-3 were increased ( Figure 4E, P = 0.001 in T24, by regulating the expression of multiple genes. [22][23][24][25][26] GREB1 is shown to be one of the most oestrogen-specific genes and plays an important role in oestrogen-mediated transcriptional activation. The corresponding enhancer of GREB1 could transcribe into eGREB1 when exposed to oestrogen.…”