ARID1A-mutated ovarian cancers depend on HDAC6 activity
ARID1A , encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be expl...
Saved in:
Published in | Nature cell biology Vol. 19; no. 8; pp. 962 - 973 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.08.2017
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | ARID1A
, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers.
ARID1A
and
TP53
mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in
ARID1A
-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing
ARID1A
-mutated tumours. This correlated with the suppression of growth and dissemination of
ARID1A
-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in
ARID1A
-mutated cells correlated with a direct transcriptional repression of
HDAC6
by ARID1A. HDAC6 inhibition selectively promoted apoptosis of
ARID1A
-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus,
ARID1A
mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for
ARID1A
-mutated cancers.
Bitler
et al.
show that HDAC6 activity is essential for the survival of ovarian cancer cells carrying loss-of-function ARID1A mutation, thus representing a promising therapeutic target. |
---|---|
Bibliography: | These authors contributed equally to this work. |
ISSN: | 1465-7392 1476-4679 |
DOI: | 10.1038/ncb3582 |