ARID1A‐deficient cells require HDAC6 for progression of endometrial carcinoma

Abstract

AT‐rich interactive domain‐containing protein 1A (ARID1A) loss‐of‐function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas. However, the molecular mechanisms linking these genetic changes to the altered pathways regulating tumour initiation, maintenance and/or progression remain poorly understood. Thus, the main aim of this study was to analyse the role of ARID1A loss of function in endometrial tumorigenesis. Here, using different endometrial in vitro and in vivo models, such as tumoral cell lines, 3D primary cultures and metastatic or genetically modified mouse models, we show that altered expression of ARID1A is not enough to initiate endometrial tumorigenesis. However, in an established endometrial cancer context, ARID1A loss of function accelerates tumoral progression and metastasis through the disruption of the G2/M cell cycle checkpoint and ATM/ATR‐mediated DNA damage checkpoints, increases epithelial cell proliferation rates and induces epithelial mesenchymal transition through the activation of histone deacetylase 6 (HDAC6). Next, we demonstrated that the inhibition of HDAC6 function, using the HDAC6‐specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A‐ knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A‐ deficient cells. In summary, the findings exposed in this work indicate that the inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A‐mutant endometrial cancer diagnosed in advanced stages.

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

“…In non-small cell carcinoma cell lines A549, LL2, and H1299, inhibition of HDAC6 by ACY-1215 leads to G2 phase arrest and increased apoptosis ( Deskin et al, 2020 ). In ARID1A-deficient endometrial carcinoma, the G2/M cell cycle checkpoint and ATM/ATR-mediated DNA damage checkpoints is disrupted, while the migratory and invasive phenotype can be reversed by ACY-1215 ( Megino-Luque et al, 2022 ). In triple-negative breast cancer, ACY-1215 results in G1 cell cycle arrest and apoptosis ( Cao et al, 2022 ), and enhances the anti-tumor effect of eribulin through tubulin acetylation ( Oba et al, 2021 ).…”

ARID1A-deficient cells promote endometrial carcinoma progression and dissemination by reprograming tumor microenvironment

“…Western blotting analysis were performed as described previously 23 . Briefly, cells were washed with cold PBS and lysed with lysis buffer (Tris HCl 50mM, NaCl 150mM, 1% de Tritón X-100, 0,1% de SDS, EDTA 1mM) and sonicated.…”

“…Specifically, ARID1A mutations occurs with high frequency in gynecological cancers, with a mutational frequency of 46,7% observed in low-grade EEC, rising to 60% in highgrade EEC 11 . Although the role of ARID1A in EC is not fully understand, recent findings suggest that in EEC, ARID1A participate in tumor progression rather than initiation 9,12,13 .…”

“…Specifically, ARID1A mutations occurs with high frequency in gynecological cancers, with a mutational frequency of 46,7% observed in low-grade EEC, rising to 60% in high-grade EEC 11 . Although the role of ARID1A in EC is not fully understand, recent findings suggest that in EEC, ARID1A participate in tumor progression rather than initiation 9,12,13 . Given the important role of ARID1A a better characterization of ARID1A lost effect in endometrial tumor progression is critical to improve ARID1A mutation EC treatments.…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…B-109, in combination with HDAC6 inhibition, synergistically inhibited the growth of ARID1A-inactivated OCCCs [ 94 ]. ARID1A-deficient EC cells were shown to require HDAC6 for progression [ 95 ]. ARID1A repressed the expression of PD-L1 [ 96 ].…”