ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells

Abstract

Background ARID1A (AT-rich interactive domain-containing protein 1A) is a subunit of the BAF chromatin remodeling complex and plays roles in transcriptional regulation and DNA damage response. Mutations in ARID1A that lead to inactivation or loss of expression are frequent and widespread across many cancer types including colorectal cancer (CRC). A tumor suppressor role of ARID1A has been established in a number of tumor types including CRC where the genetic inactivation of Arid1a alone led to the formation of invasive colorectal adenocarcinomas in mice. Mechanistically, ARID1A has been described to largely function through the regulation of enhancer activity. Methods To mimic ARID1A-deficient colorectal cancer, we used CRISPR/Cas9-mediated gene editing to inactivate the ARID1A gene in established colorectal cancer cell lines. We integrated gene expression analyses with genome-wide ARID1A occupancy and epigenomic mapping data to decipher ARID1A-dependent transcriptional regulatory mechanisms. Results Interestingly, we found that CRC cell lines harboring KRAS mutations are critically dependent on ARID1A function. In the absence of ARID1A, proliferation of these cell lines is severely impaired, suggesting an essential role for ARID1A in this context. Mechanistically, we showed that ARID1A acts as a co-factor at enhancers occupied by AP1 transcription factors acting downstream of the MEK/ERK pathway. Consistently, loss of ARID1A led to a disruption of KRAS/AP1-dependent enhancer activity, accompanied by a downregulation of expression of the associated target genes. Conclusions We identify a previously unknown context-dependent tumor-supporting function of ARID1A in CRC downstream of KRAS signaling. Upon the loss of ARID1A in KRAS -mutated cells, enhancers that are co-occupied by ARID1A and the AP1 transcription factors become inactive, thereby leading to decreased target gene expression. Thus, targeting of the BAF complex in KRAS -mutated CRC may offer a unique, previously unknown, context-dependent therapeutic option in CRC. Electronic supplementary material The online version of this article (10.1186/s13148-019-0690-5) contains supplementary material, which is available to authorized users.

Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

“…We then performed motif enrichment analysis by using the AME algorithm [26] on each group of ATAC peaks. Interestingly, we found that the binding motifs of SRY, FOX family, CDX1, SOX5, etc., were enriched in the ATAC peaks with significantly increased accessibility in ARID1A-KO cells (Figure 5F, and Supplementary File 7), which is consistent with the results of a recent study showing ARID1A as a co-factor of AP-1 [27].…”

Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis

“…Similarly, concomitant bi-allelic deletion of Arid1a in the Apc min mice significantly inhibited intestinal neoplasia [33]. In addition, CRISPR-mediated deletion of ARID1A in human colorectal cancer cells with KRAS mutations significantly reduced proliferation, accompanied by attenuation of MEK/ERK dependent transcriptional signaling [34]. ARID1A mutations also correlated with better survival in uterine corpus endometrial carcinoma [35].…”

Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression

“…Our RT-qPCR results showed that overexpression of candidate transcription factors E2F1, ELK1, NFκB, Oct4, Sp1 or STAT3 did not influence ZNF322A mRNA expression. However, it is still possible that other TF candidates, for example c-jun or c-myc, which has been shown to cooperate with mutated Kras 28 - 30 , may play a role in regulating ZNF322A transcription. Whether YY1 need additional TF or transcription co-regulators to drive ZNF322A transcription is worthy of further investigation.…”