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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.

SUBMITTER: Sen M

PROVIDER: S-EPMC6585056 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Sen Madhobi M Wang Xin X Hamdan Feda H FH Rapp Jacobe J Eggert Jessica J Kosinsky Robyn Laura RL Wegwitz Florian F Kutschat Ana Patricia AP Younesi Fereshteh S FS Gaedcke Jochen J Grade Marian M Hessmann Elisabeth E Papantonis Argyris A Strӧbel Philipp P Johnsen Steven A SA

Clinical epigenetics 20190619 1

<h4>Background</h4>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 ...[more]

PMID: 31217031

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Project description:BackgroundColorectal cancer standed as a global health challenge, ranking third in cancer incidence and second in cancer-related deaths worldwide. A deeper understanding of the intricate mechanisms driving colorectal cancer development was pressing need. STK16 had garnered attention in recent researches, while its involvement in cancer had been minimally explored. c-MYC had emerged as a key player in cancer biology. Due to its complex structure, multifunctionality, and intricate interactions, directly inhibiting the activity of c-MYC proves to be challenging. Hence, current research was directing efforts towards modulating c-MYC expression levels.MethodsImmunoblot, Immunohistochemistry and immunoprecipitation assays were conducted to assess the indicated protein expression levels. RT-PCR was performed to detect the corresponding mRNA expression levels. The proliferation, migration, invasion, and colony formation abilities of the specified cancer cells were investigated using CCK8 assays, Brdu assays, transwell assays, and colony formation assays, respectively. Cellular and animal experiments were performed to investigate the correlation between STK16 signaling and c-MYC signaling.ResultsSTK16 plays a positive regulatory role in the progression of colorectal cancer. Delving into the molecular mechanisms, we unveiled that STK16 phosphorylated c-MYC at serine 452, a pivotal event hindering the ubiquitin-proteasome pathway degradation of c-MYC. Importantly, colorectal cancer proliferation mediated by STK16 was found to be dependent on the phosphorylation of c-MYC at S452. Furthermore, the researchers demonstrated that STK16 knockout or pharmacological inhibition significantly curtailed colorectal cancer proliferation and c-MYC expression in in vivo animal models.ConclusionWe discovered that STK16 phosphorylates c-MYC at serine 452, hindering its degradation via the ubiquitin-proteasome pathway. STK16 inhibition, either genetically or pharmacologically, effectively curtails cancer growth and c-MYC expression in vivo. These findings highlight STK16 as a potential therapeutic target for colorectal cancer.

Project description:Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing of in vivo cutaneous wounds and closure of in vitro scratch wounds in murine embryonic fibroblast (MEF) monolayers were delayed in 129, but not B6, TG2 knockouts, relative to their wild-type counterparts, with wound closure in 129 being faster than in B6 wild-types. A single dose of exogenous recombinant wild-type TG2 to 129 TG2-/- mice or MEFs immediately post-wounding accelerated wound closure. Neutrophil and monocyte recruitment to 129 cutaneous wounds was not affected by Tgm2 deletion up to 5 days post-wounding. Tgm2 mRNA and TG2 protein abundance were higher in 129 than in B6 wild-types and increased in abundance following cutaneous and scratch wounding. Tgm1 and factor XIIA (F13A) mRNA abundance increased post-wounding, but there was no compensation by TG family members in TG2-/- relative to TG2+/+ mice in either strain before or after wounding. 129 TG2+/+ MEF adhesion was greater and spreading was faster than that of B6 TG2+/+ MEFs, and was dependent on syndecan binding in the presence, but not absence, of RGD inhibition of integrin binding. Adhesion and spreading of 129, but not B6, TG2-/- MEFs was impaired relative to their wild-type counterparts and was accelerated by exogenous addition or transfection of TG2 protein or cDNA, respectively, and was independent of the transamidase or GTP-binding activity of TG2. Rho-family GTPase activation, central to cytoskeletal organization, was altered in 129 TG2-/- MEFs, with delayed RhoA and earlier Rac1 activation than in TG2+/+ MEFs. These findings indicate that the rate of wound healing is different between 129 and B6 mouse strains, correlating with TG2 abundance, and although not essential for wound healing, TG2 facilitates integrin- and syndecan-mediated RhoA- and Rac1-activation in fibroblasts to promote efficient wound contraction.

Dataset Information

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

Publications

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

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