Novel SCLC tumour suppressor gene discovered

By Lynda Williams, Senior medwireNews Reporter

Inactivation of the MYC-associated factor X gene, MAX, may play a significant role in the development of small-cell lung cancer (SCLC), scientists believe.

Intragenic homozygous deletions leading to the loss of the MAX protein were identified in four SCLC lines, as well as in 6% of 98 primary SCLC surgical tissue samples tested, the team reports in Cancer Discovery.

“The alterations were tumor-specific and homozygous, leaving little doubt that MAX constitutes a bona fide tumor-suppressor gene,” write Montse Sanchez-Cespedes (Hospitalet de Llobregat, Barcelona, Spain) and co-authors.

Although MAX forms a heterodimer with MYC protein, which is also known to be mutated in some SCLC patients, there were no concomitant MYC mutations. Nor were there mutual mutations of MAX and BRG1, which codes for an ATPase in the switch/sucrose nonfermentable (SWI/SNF) complex. The complex plays a role in nucleosome remodelling and is thought to act as a tumour suppressor in up to 20% of human malignancies.

“The functional relationship of MYC with BRG1 and with the SWI/SNF complex is well established,” the team explains. BRG1 regulates expression of MYC and MYC target genes and loss of BRG1 function prevents cell differentiation, while MYC, in turn, interacts with a SWI/SNF component.

When the researchers knocked out BRG1 in SCLC cell lines with MAX mutations, cell growth was significantly reduced by over 95%, whereas cell viability was only moderately reduced by the loss of BRG1 in wild-type cell lines, demonstrating that loss of both genes heralds “a synthetic lethal interaction”.

“This information suggests therapeutic possibilities for the treatment of patients with SCLC, and possibly for patients with pheochromocytoma, with MAX-deficient tumors,” they suggest.

Moreover, the researchers demonstrated that BRG1 was necessary for the MAX dimerization protein, as well as MAX activation of neuroendocrine transcription and upregulation of MYC targets, including glycolysis genes.

“This constitutes the first demonstration of a direct functional connection between these two tumor suppressors,” Sanchez-Cespedes et al observe.

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
New imaging method could transform gene expression research