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Amino Acid Deprivation-Induced Autophagy Requires Upregulation of DIRAS3 through Reduction of E2F1 and E2F4 Transcriptional Repression

1
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
2
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
3
Office of Translational Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(5), 603; https://doi.org/10.3390/cancers11050603
Received: 13 March 2019 / Revised: 19 April 2019 / Accepted: 26 April 2019 / Published: 30 April 2019
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Abstract

Failure to cure ovarian cancer relates to the persistence of dormant, drug-resistant cancer cells following surgery and chemotherapy. “Second look” surgery can detect small, poorly vascularized nodules of persistent ovarian cancer in ~50% of patients, where >80% are undergoing autophagy and express DIRAS3. Autophagy is one mechanism by which dormant cancer cells survive in nutrient poor environments. DIRAS3 is a tumor suppressor gene downregulated in >60% of primary ovarian cancers by genetic, epigenetic, transcriptional and post-transcriptional mechanisms, that upon re-expression can induce autophagy and dormancy in a xenograft model of ovarian cancer. We examined the expression of DIRAS3 and autophagy in ovarian cancer cells following nutrient deprivation and the mechanism by which they are upregulated. We have found that DIRAS3 mediates autophagy induced by amino acid starvation, where nutrient sensing by mTOR plays a central role. Withdrawal of amino acids downregulates mTOR, decreases binding of E2F1/4 to the DIRAS3 promoter, upregulates DIRAS3 and induces autophagy. By contrast, acute amino acid deprivation did not affect epigenetic regulation of DIRAS3 or expression of miRNAs that regulate DIRAS3. Under nutrient poor conditions DIRAS3 can be transcriptionally upregulated, inducing autophagy that could sustain dormant ovarian cancer cells. View Full-Text
Keywords: DIRAS3; ARHI; autophagy; ovarian cancer; amino acid deprivation; tumor dormancy; mTOR; nutrient sensing DIRAS3; ARHI; autophagy; ovarian cancer; amino acid deprivation; tumor dormancy; mTOR; nutrient sensing
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Sutton, M.N.; Huang, G.Y.; Zhou, J.; Mao, W.; Langley, R.; Lu, Z.; Bast, R.C., Jr. Amino Acid Deprivation-Induced Autophagy Requires Upregulation of DIRAS3 through Reduction of E2F1 and E2F4 Transcriptional Repression. Cancers 2019, 11, 603.

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