MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis

Kalkat, Manpreet; Resetca, Diana; Lourenco, Corey; Chan, Pak-Kei; Wei, Yong; Shiah, Yu-Jia; Vitkin, Natasha; Tong, Yufeng; Sunnerhagen, Maria; Done, Susan J.; Boutros, Paul C.; Raught, Brian; Penn, Linda Z.

doi:10.1016/j.molcel.2018.09.031

Cited by 154 publications

(177 citation statements)

References 69 publications

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“…The mechanisms by which Yap/Taz and MYC coregulate transcription remain to be addressed: most noteworthy in this regard, these factors interact with an overlapping set of general coregulators (e.g., BRD4, p300, p400, RUVBL1, KMT2D, SAP18 or the SWI/ SNF complex). (39,40) As exemplified by BRD4, these coregulators may be involved in wider transcriptional programs than the transcription factors themselves, (41,42) but may nonetheless be particularly critical for transcription of genes activated by either Yap/Taz, (39) MYC, (43) or-even most likely-both together. (31) Although the involvement of MYC, WNT/βcatenin, and Yap/Taz in liver tumorigenesis was amply documented, (3,13,31,(44)(45)(46)(47)(48) their mutual interplay-if any-remained to be unraveled.…”

Section: Discussionmentioning

confidence: 99%

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

et al. 2020

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BaCKgRoUND aND aIMS: Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. appRoaCH aND ReSUltS: We generated a mouse model allowing conditional activation of MYC and WNT/ β-catenin signaling (through either β-catenin activation or loss of APC-adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

et al. 2020

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“…The upregulation of Myc could be present in various types of cancers, such as colon, breast, lung and gastric cancer [68]. To date, Myc and ANLN have been discovered to interact through experimental evidence, including affinity capture-MS [69], and proximity label-MS [70] and curated by the Biogrid [63].…”

Section: Other Binding Partnersmentioning

confidence: 99%

“…Among other actin-binding proteins present in the nucleus, FLi1 homolog, α-actinin 4, and filamin A are associated with SWI/SNF, estrogen receptor α, and BRCA 1, 2, respectively, and are involved in chromatin remodeling, transcription regulation, and DNA damage repair, respectively (Figure 4) [83]. ANLN is also known to bind transcription factors such as TAF10, Myc, and BRCA1, so ANLN is likely to be involved in chromatin organization, transcription, and DNA damage repair in the nucleus, respectively [70,92]. Recent reports found that the regulation of actin polymerization in the nucleus is required for transcription activation, cell cycle progression and DNA repair [106,107].…”

Section: Anln In Nucleusmentioning

confidence: 99%

Role of Anillin in Tumour: From a Prognostic Biomarker to a Novel Target

Tuan

Lee

2020

Cancers

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Anillin (ANLN), an actin-binding protein, reportedly plays a vital role in cell proliferation and migration, particularly in cytokinesis. Although there have been findings pointing to a contribution of ANLN to the development of cancer, the association of ANLN to cancer remains not fully understood. Here, we gather evidence to determine the applicability of ANLN as a prognostic tool for some types of cancer, and the impact that ANLN has on the hallmarks of cancer. We searched academic repositories including PubMed and Google Scholar to find and review studies related to cancer and ANLN. The conclusion is that ANLN could be a potent target for cancer treatment, but the roles ANLN, other than in cytokinesis and its influence on tumour microenvironment remodeling in cancer development, must be further elucidated, and specific ANLN inhibitors should be found.

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“…All three MYC proteins have essentially the same overall domain structure, [74][75][76] consisting of…”

Section: Structurementioning

confidence: 99%

Drugging “undruggable” genes for cancer treatment: Are we making progress?

Duffy

Crown

2020

Intl Journal of Cancer

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RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as "undruggable." Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.

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MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis

Cited by 154 publications

References 69 publications

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz

Role of Anillin in Tumour: From a Prognostic Biomarker to a Novel Target

Drugging “undruggable” genes for cancer treatment: Are we making progress?

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