ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives liver cancer cell metastasis

Abstract

ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including liver cancer. Previous studies have demonstrated that ARID1A deficiency can cause liver cancer metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms remain poorly understood. To address the effect of Arid1a deficiency on chromatin organization, we generated chromatin interaction matrices, and exploited the conformation changes upon Arid1a depletion in hepatocytes. Our results demonstrated that Arid1a deficiency induced A/B compartment switching, topologically associated domain (TAD) remodeling, and decrease of chromatin loops. Further mechanism studies revealed that ATPase BRG1 of SWI/SNF complex could physically interact with RAD21, a structural subunit of chromatin architectural element cohesin; whereas ARID1A deficiency significantly diminished the coupled BRG1-RAD21. Interestingly, the tumor-associated genes within the switched compartments were differentially expressed depending upon Arid1a depletion or not. As a consequence of ARID1A deficiency-induced conformational alteration, the dysregulation of some genes such as PMP22 and GSC, promoted the invasion capacity of liver cancer cells. This study provides an insight into liver cancer tumorigenesis and progression related to ARID1A mutations.

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

“…To further analyse whether Arid1a could directly regulate Il1a expression，we downloaded the deposited Arid1a ChIP‐seq data. 30 The analysed data demonstrated that ARID1A has enrichment on the site where Il1a showing a significant peak gain after Arid1a deletion in our ATAC‐seq, suggesting that ARID1A could directly regulate Il1a expression (Figure 4C ). Taken together, these data indicated that microglial abnormality in the absence of Arid1a during development affected neuronal differentiation and cytokines secretion.…”

“…Genome‐browser view of ATAC‐seq showed a significant peak gain of Il1a (Figure 4C), but not Il6 (Figure S1 H). To further analyse whether Arid1a could directly regulate Il1a expression，we downloaded the deposited Arid1a ChIP‐seq data 30 . The analysed data demonstrated that ARID1A has enrichment on the site where Il1a showing a significant peak gain after Arid1a deletion in our ATAC‐seq, suggesting that ARID1A could directly regulate Il1a expression (Figure 4C).…”

Epigenetic regulation in cancer

“…The chromatin remodeler SMARCA4, for instance, has been validated as a tumor suppressor, with its diminished expression linked to enhanced colorectal cancer metastasis via the Wnt/β‐catenin signaling pathway 171 . Moreover, the attenuation of ARID1A has been shown to propel liver cancer cell metastasis by disrupting the SMARCA4–RAD21 interaction 172 . Intriguingly, ARID1A exhibits dualistic roles in oncogenesis—it is necessary for the initial stages of HCC yet acts to thwart tumor progression and metastasis in advanced stages, highlighting the intricate, stage‐dependent functions of ARID1A in cancer and the need for nuanced treatment strategies 173 .…”

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

“…ARID1A is another essential subunit in SWI/SNF subfamily, whose deficiency promotes cell migration and invasion in lung adenocarcinoma (LUAD) [ 143 ] as well as in breast cancer cells [ 144 ]. In addition, Shang et al demonstrated that ARID1A knockdown drives the metastasis of liver cancer cells by weakening SMARCA4-RAD21 interaction [ 145 ]. Notably, Sun et al found that ARID1A has context-dependent tumor-suppressive and oncogenic roles.…”