Autophagy/Mitophagy Regulated by Ubiquitination: A Promising Pathway in Cancer Therapeutics

SIMPLE SUMMARY: Autophagy and mitophagy are important processes in the regulation of cancer progression. Although autophagy and mitophagy have dual roles in cancer, targeting their regulation has potential for developing an effective cancer treatment strategy. Thus, it is important to understand how ubiquitination and deubiquitination of autophagy-related proteins are regulated to exploit autophagy and mitophagy during cancer development. ABSTRACT: Autophagy is essential for organismal development, maintenance of energy homeostasis, and quality control of organelles and proteins. As a selective form of autophagy, mitophagy is necessary for effectively eliminating dysfunctional mitochondria. Both autophagy and mitophagy are linked with tumor progression and inhibition. The regulation of mitophagy and autophagy depend upon tumor type and stage. In tumors, mitophagy has dual roles: it removes damaged mitochondria to maintain healthy mitochondria and energy production, which are necessary for tumor growth. In contrast, mitophagy has been shown to inhibit tumor growth by mitigating excessive ROS production, thus preventing mutation and chromosomal instability. Ubiquitination and deubiquitination are important modifications that regulate autophagy. Multiple E3 ubiquitin ligases and DUBs modulate the activity of the autophagy and mitophagy machinery, thereby influencing cancer progression. In this review, we summarize the mechanistic association between cancer development and autophagy/mitophagy activities regulated by the ubiquitin modification of autophagic proteins. In addition, we discuss the function of multiple proteins involved in autophagy/mitophagy in tumors that may represent potential therapeutic targets.