In recent years, a paradigm shift in cancer biology has emerged through the spotlight on acetylation modification and its intricate interplay with autophagy. Once regarded primarily as separate cellular processes—acetylation as a post-translational modification influencing protein function, and autophagy as a catabolic pathway maintaining cellular homeostasis—new research uncovers a dynamic interconnection that profoundly shapes tumorigenesis at multiple stages. This crosstalk not only modulates fundamental aspects of cancer biology like tumor initiation, progression, drug resistance, prognosis, and the tumor microenvironment, but also unveils promising avenues for therapeutic interventions.
At the onset of tumorigenesis, the acetylation–autophagy axis exerts multifaceted regulatory roles, as demonstrated in hepatocellular carcinoma (HCC). Here, the deacetylase SIRT1 targets p62 at lysine residue 295 to prevent its degradation, thereby activating mTORC1, a major growth-promoting kinase complex, which accelerates liver cancer development. Conversely, acetyltransferase PCAF counters oncogenic signaling by enhancing autophagic flux through suppression of the Akt/mTOR pathway, ultimately triggering cancer cell death. This dual mechanism underscores the delicate balance acetylation imparts upon autophagic processes, effectively influencing tumor initiation by modulating both signaling networks and proteostasis.
Breast cancer further exemplifies this acetylation-autophagy synergy. The transcriptional coactivator p300 is recruited by HBXIP to acetylate HOXB13 at a key lysine residue (K277), stabilizing the transcription factor by preventing its chaperone-mediated autophagic degradation. This stabilization propels ERα-dependent proliferation, highlighting how acetylation safeguards oncogenic drivers from degradation to foster tumor initiation. Similarly, the acetylation of MST1 plays a tumor-suppressive role by maintaining its stability within the Hippo signaling pathway; perturbations in this acetylation facilitate cancer onset by dysregulating cell proliferation and apoptosis pathways.
Colorectal cancer (CRC) paints an intricate picture where metabolic enzymes are targeted by acetylation to shape autophagic pathways pivotal for tumor growth dynamics. PINK1-driven mitophagy reduces intracellular acetyl-CoA pools, suppressing metabolic reprogramming and tumor expansion. Elevated acetyl-CoA, however, reverses this suppression, emphasizing a metabolic tug-of-war influenced by acetylation status. Furthermore, SIRT5-mediated deacetylation of LDHB enhances lactate dehydrogenase activity and autophagy, fostering CRC progression. Acetylation at specific residues can destabilize enzymes like SHMT2, prompting lysosomal degradation and limiting serine metabolism—processes tightly linked to autophagic regulation and cancer cell proliferation.
Beyond initiation, acetylation-autophagy crosstalk governs tumor advancement by influencing cellular invasiveness and metastatic potential. Melanoma cells manipulate fatty acid oxidation-derived acetyl-CoA to regulate autophagosome formation, facilitating migration and invasion. SIRT1’s deacetylation of Beclin1 promotes epithelial-mesenchymal transition (EMT) by accelerating E-cadherin degradation, a hallmark of increased invasiveness; interruption of autophagy reverses this aggressive phenotype. In breast and prostate cancers, acetylation-dependent chaperone-mediated autophagic degradation of HSD17B4 reduces its accumulation, suppressing migratory capabilities. Similar modulatory mechanisms involving SIRT1 and ACAT1 tweak mitophagy and protein stability to either hinder or exacerbate tumor progression, demonstrating how finely acetylation tunes autophagy to dictate cancer cell behavior.
The resilience of tumors in the face of therapeutics—drug resistance—is another battleground shaped by acetylation-autophagy interplay. In breast cancer, CREBBP-mediated acetylation of the autophagic regulator RB1CC1 fortifies autophagic pathways to support survival under stress, enhancing resistance. HBXIP-induced activation of HDAC6 deacetylates MST1, disrupting tumor-suppressive Hippo signaling and driving resistance to tamoxifen, a key endocrine therapy. Triple-negative breast cancers exploit elevated H3K27 acetylation to upregulate DDIT4-AS1, which in turn activates autophagy to evade paclitaxel-mediated cytotoxicity. Prostate cancer proteomes illustrating acetylation-modulated chaperone-mediated autophagy reflect a selective suppression of macroautophagy, allowing tumor cells to withstand therapeutic insults via stress adaptation.
Prognostic landscapes in cancers such as liver, cervical, pancreatic, glioblastoma, colorectal, and gastric cancers can be inferred through the lens of acetylation-autophagy signaling. For instance, heightened PCAF-driven histone H4 acetylation in liver cancer corresponds to enhanced autophagic activity and improved clinical outcomes. In parallel, acetylation of Parkin by ACAT1 supports mitophagy and mitochondrial integrity, correlating with favorable prognosis in cervical cancer. Conversely, aberrations like diminished LDH-A acetylation in pancreatic tumors stabilize glycolytic enzymes, fueling tumor metabolism and heralding poor prognosis. Glioblastomas showing ARD1-mediated acetylation of PGK1 augment autophagy that corresponds with malignant progression. Together, these examples demonstrate the prognostic potency embedded within acetylation-autophagy regulatory nodes.
Within the tumor microenvironment (TME), the acetylation-autophagy nexus orchestrates complex interactions between cancer cells and the surrounding stromal, immune, and extracellular matrix components. In lung cancer, extracellular vesicles convey SIRT2 to deacetylate key extracellular matrix proteins such as integrin β3, weakening cell-matrix adhesion and facilitating metastasis. Hypoxia, a defining feature of the TME in gastric cancer peritoneal metastasis, induces autophagic degradation of SIRT1, increasing acetylation of hypoxia-inducible factors and VEGFA signaling to promote invasion. Glioblastoma cells recalibrate their metabolic stress response through ARD1-mediated acetylation of PGK1, enhancing autophagosome formation and tumor survival under nutrient deprivation. These findings underscore how acetylation-modulated autophagy integrates environmental cues to drive cancer cell adaptation and dissemination.
Immune cell functionality within the TME is equally contingent on the acetylation-autophagy axis. Autophagy coupled with histone deacetylation modulates CD8⁺ T cell effector activities, preserving a stem-like phenotype essential for sustained antitumor responses. EP300 inhibition, often triggered by pharmacological agents like aspirin, stimulates autophagy and amplifies CD8⁺ T cell immunity. Autophagy in tumor cells remodels purinergic signaling by modulating ATP and adenosine metabolism, which enhances cytotoxic T cell responses and limits regulatory T cell recruitment, effectively reshaping immunosurveillance. Moreover, in antigen-presenting cells, autophagic regulation of cGAS acetylation balances type I interferon production and PD-L1 expression, dictating the immunosuppressive milieu. The nuanced interplay between metabolism, acetylation states, and autophagic flux ultimately sculpts immune cell phenotypes in the cancer niche.
Heterogeneity within tumor types and molecular subtypes substantially informs how acetylation-autophagy dynamics manifest. Hepatocellular carcinoma prominently features SIRT1-p62 and PCAF-microtubule pathways as critical drivers, whereas breast cancer subtypes diverge, with estrogen receptor-positive tumors relying on p300-mediated stabilization of transcription factors like HOXB13, and triple-negative breast cancers leveraging histone acetylation and long noncoding RNA-driven autophagy for chemoresistance. In colorectal cancer, microsatellite instability-high (MSI-H) subtypes exploit SIRT5/LDHB-modulated metabolism, as opposed to microsatellite stable (MSS) tumors, where chromatin modifiers such as SIRT1 and SIRT7 dominate acetylation control. Prostate cancer’s androgen receptor-positive and independent subtypes also recruit distinct acetylation-autophagy pathways, emphasizing the contextual and spatial complexity in these regulatory networks.
Mechanistically, the acetylation-autophagy interplay integrates epigenetic, metabolic, and proteostatic cues, employing a repertoire of enzymes—including acetyltransferases like p300 and PCAF and deacetylases such as SIRT1, SIRT5, HDAC6—to modulate key protein targets across cellular compartments. This regulation influences ubiquitination, protein stability, autophagosome formation, and selective autophagic degradation pathways including chaperone-mediated autophagy and mitophagy. The dynamic acetylation of metabolic enzymes alters substrate availability and redox balance, while acetylation of transcription factors adjusts gene expression programs fundamental for tumor cell survival and immune evasion.
Therapeutically, the acetylation-autophagy axis offers a tantalizing target landscape. Agents modulating acetyltransferase or deacetylase activity may recalibrate autophagic processes, resensitizing tumors to chemotherapy or immunotherapy. For example, HDAC inhibitors have been shown to restore autophagy in hypoxic prostate tumors, constraining progression, while aiming at HDAC6 or SIRT1 offers a route to reverse therapy resistance in aggressive breast cancers. However, the dualistic nature of autophagy—contextually tumor-suppressive or tumor-promoting—necessitates a nuanced understanding of acetylation-dependent autophagic regulation to avoid unintended consequences.
Intriguingly, the acetylation-autophagy crosstalk extends beyond tumor cells to encompass the metabolic and epigenetic remodeling of immune cells, advocating for combinatorial therapies that engage both cancer intrinsic pathways and the immune microenvironment. Future research deciphering these multilayered networks is pivotal, potentially informing precision oncology strategies tailored to tumor subtype-specific acetylation-autophagy signatures.
In sum, the emerging insights into the intersection of acetylation and autophagy propel a comprehensive rethinking of cancer biology. This regulatory axis integrates signaling, metabolism, and epigenetics, threading through tumor initiation, progression, drug resistance, prognosis, and immune evasion. Its modularity across cancer types underscores both its fundamental biological significance and its promise as a therapeutic frontier. Ongoing studies will undoubtedly refine our grasp of this complex interplay, guiding innovative interventions to improve patient outcomes.
Subject of Research: Crosstalk between acetylation modification and autophagy in cancer biology
Article Title: Crosstalk between acetylation modification and autophagy in cancer: roles, mechanisms, and therapeutic potential
Article References:
Liu, Y., Yan, Z., Fu, Z. et al. Crosstalk between acetylation modification and autophagy in cancer: roles, mechanisms, and therapeutic potential. Cell Death Discov. 11, 522 (2025). https://doi.org/10.1038/s41420-025-02809-x
Image Credits: AI Generated
DOI: 10 November 2025
