Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation

Abstract

Activation of cancer-associated fibroblasts (CAFs) promotes tumorigenesis. Kim et al. show that ATF3 and CSL converge in negative regulation of CAF activation through long-distance chromatin control. Bromodomain and extra-terminal (BET) inhibitors counteract the effects of ATF3 and CSL loss in CAF activation and cancer–stromal cell expansion.

Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation

“…Parallel downmodulation of AR and CSL in dermal fibroblasts underlying premalignant and malignant skin cancer lesions and various CAFs raised the possibility of a reciprocal cross-regulation. Immunoblot and RT-qPCR analysis showed consistent suppression of AR expression, at both mRNA and pro- we previously reported in HDF with decreased CSL levels (6). In fact, ChIP analysis of HDFs with CSL gene silencing versus controls showed an increase of the repressive histone mark H3K9Me3 and a decrease of the active histone mark H3K27Ac at the AR pro-tein levels, in multiple HDF strains with CSL knockdown ( Figure 11, A and B).…”

“…Alterations of key regulators of transcription and chromatin organization involved in early steps of CAF activation include downmodulation of CSL/RBP-Jκ (subsequently called CSL), the key effector of Notch signaling endowed with intrinsic transcriptional-repressive function and overall determinant of chromatin configuration (5,6). CSL functions as a direct negative regulator of many CAF effector genes and at the same time binds to p53, suppressing its activity (5).…”

Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway

“…Our co-culture and conditioned medium assays demonstrated that ATF3-overexpressing HDFs blocked both Mel-JuSo and UACC62 melanoma cell proliferation and migration through a paracrine signaling pathway. It is well-known that ATF3, a transcriptional repressor, negatively regulates expression of numerous cytokines in immune cells (16,45,46); also skin dermal fibroblasts with ATF3 deletion upregulated CAF effector genes including cytokines and matrix metalloproteases (33). Therefore, we examined these genes in our system and confirmed that expression of CAFrelated cytokines such as IL-6, IL-8 and COX1/2 were decreased in ATF3-overexpressing HDFs, and increased in ATF3-deleted HDFs.…”

“…However, the role of ATF3 in tumor stromal cells has been little explored so far. Just recently, Kim et al investigated ATF3 function in stromal fibroblasts of skin SCC and found ATF3 deletion in skin fibroblasts were prone to develop aggressive chemically-induced skin tumors with enhanced CAF activation (33). Avraham et al reported that double deletion of ATF3 and JDP2 in mouse CAFs promoted tumor growth (17).…”

“…Decreased the Expression of IL-6, IL-8, and Other Cytokines in HDFs ATF3 has previously been shown to downregulate expression of many cytokines including IL-6 and IL-8 (33). Therefore, we examined the effects of ATF3 levels on the expression of potentially relevant cytokines and growth factors in HDFs.…”