A quarterly publication of the Autism Research Institute

The Autism Research Review International is quarterly publication of the Autism Research Institute

Spring, 2018 | Number 2, Volume 32

Anti-cancer drug reverses social deficits for an extended period in a mouse model of autism

Researchers at the University at Buffalo in New York report that brief treatment with a very low dose of the anti-cancer drug romidepsin can ameliorate social deficits for an extended period of time in animal models of autism. 

Luye Qin and colleagues, including senior author Zhen Yan, found that three days of treatment led to three weeks of improvement in mice deficient in a gene called Shank 3—a time span covering the juvenile to late adolescent period. This is equivalent, they say, to several years in humans. 

Earlier, the same research team discovered that the loss of Shank 3 disrupts neuronal communications and causes social deficits by affecting the function of the NMDA (n-methyl-D-aspartate) receptor—a receptor that plays a crucial role in regulating cognition and emotion. In the new study, the researchers found that romidepsin could reverse these deficits by restoring gene expression and function via an epigenetic mechanism. (Epigenetic changes increase or decrease the function of a gene without altering DNA structure.) 

Many mutations involved in ASD result from chromatin remodeling factors, which change the structure of chromatin—the genetic material in the cell nucleus that condenses into chromosomes. “The extensive overlap in risk genes for autism and cancer, many of which are chromatin remodeling factors, supports the idea of repurposing epigenetic drugs used in cancer treatment as targeted treatments for autism,” Yan says. 

The researchers explored the effects of a type of chromatin remodeler called histone modifiers. These modify proteins called histones that help to organize genetic material in the nucleus in order to regulate gene expression. In particular, they focused on histone deacetylase (HDAC), a family of histone modifiers that are involved in the remodeling of chromatin structure and the transcriptional regulation of targeted genes. 

“In the autism model,” Yan says, “HDAC2 is abnormally high, which makes the chromatin in the nucleus very tight, preventing genetic material from accessing the transcriptional machinery it needs to be expressed. Once HDAC2 is upregulated, it diminishes genes that should not be suppressed, and leads to behavioral changes, such as the autism-like social deficits.” Romidepsin, a highly potent HDAC inhibitor, reduces the effects of HDAC2. 

“The HDAC inhibitor loosens up the densely packed chromatin so that the transcriptional machinery gains access to the promoter area of the genes; thus, they can be expressed,” Yan says. 

The researchers found that romidepsin had widespread effects on gene expression. When they conducted genome-wide screening, they found that it restored the majority of the more than 200 genes that were suppressed in the animal model of autism they used. 

Yan concludes, “We have discovered a small molecule compound that shows a profound and prolonged effect on autism-like social deficits without obvious side effects, while many currently used compounds for treating a variety of psychiatric diseases have failed to exhibit the therapeutic efficacy for this core symptom of autism.” 


“Social deficits in Shank3-defi cient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition,” Luye Qin, Kaijie Ma, Zi-Jun Wang, Zihua Hu, Emmanuel Matas, Jing Wei, and Zhen Yan, Nature Neuroscience, March 12, 2018 (online). Address: Zhen Yan, [email protected]


 “Autism’s social deficits are reversed by an anti-cancer drug,” news release, University at Buffalo, March 12, 2018.